OA12782A - Oxo-azabicyclic compounds. - Google Patents

Abstract

A compound selected from those of formula (I): formula (I) wherein: - X1, X2, and X3, represent N or CR3 in which R3 is as described in the description, - G1 represents a group selected from those of formulae (i/a) and (i/b): formula (II) in which R4, R5, and R6 are as defined in the description, - G2 represents a group selected from carbon-carbon triple bond, -CH=C=CH-, C=O, C=S, S(O)nt in which n1 represents an integer from 0 to 2 inclusive, or a group of formula (i/c): formula (III) in which Y1 represents O, S, -NH or Nalkyl, and Y2 represents O, S, -NH or Nalkyl, - n is an integer from 0 to 6 inclusive, and m is an integer from 0 to 7 inclusive, Z1 represents CR9R10, wherein R9 and R10 are as defined in the description, - A represents a ring system, - R1 represents a group selected from H, alkyl, alkenyl, alkynyl, optionally substituted and the group of formula (i/d): formula (IV) in which p, Z2, B, q and G3 are as defined in the description and optionally, its optical isomers, N-oxide, and addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same are useful as specific inhibitors of type-13 matrix mettaloprotease.

Description

012782 1

TITLE O F THE INVENTION . Oxo-azabicyclic compounds

FIELD O F THE INVENTION

The présent invention relates to novel oxo azabicyclic compounds which are useful5 for preparmg médicinal products for treating complaints involving a therapy with a matrixmetalloprotease-13 (MMP-13) inliibitor. These médicinal products are useful in particularfor treating certain inflammatory conditions such as rheumatoid arthritis or osteoarthritis, as well as certain proliférative conditions such as cancers.

TECHNOLOGICAL BACKGROUND OF THE INVENTION 10 Matrix métalloprotéases (MMPs) are enzymes which are involved in the renewal of extracellular 'matrix tissue, such as cartilage, tendons and joints. MMPs bring about thedestruction of the extracellular matrix tissue, which is compensated for, in a non-pathological physiological State, by its simultaneous régénération.

Under normal physiological conditions, the activity of these extremely aggressive 15 peptidases is controlled by specialized proteins which inhibit MMPs, such as the tissueinhibitors of metalloprotease (TIMPs).

Local equilibrium of the activities of MMPs and of TIMPs is critical for the renewalof the extracellular matrix. Modifications of this equilibrium which resuit in an excess ofactive MMPs, relative to their inhibitor, induce a pathological destruction of cartilage, 20 which is observed in particular in rheumatoid arthritis and in osteoarthritis.

In pathological situations, an irréversible dégradation of articular cartilage takesplace, as is the case in rheumatic diseases such as rheumatoid arthritis or osteoarthritis. Inthese pathologies, the cartilage dégradation process prédominâtes, Ieading to a destructionof the tissue and resulting in a loss of function. 25 At least twenty different matrix métalloprotéases hâve been identified to date and are subdivided into four groups, the collagénases, the gelatinases, the stromelysins and themembrane-type MMPs (MT-MMPs), respectively. 012782 2

Matrix metalloprotease-13 (MMP-13) is a collagenase-type MMP which constitutesthe prédominant collagénase observed during osteoarthritis, in the course of winchpathology the chondrocyte directs the destruction of cartilage.

There is a need for novel MMP inhibitors, more particularly for MMP-13 inhibitors,in order to prevent and/or correct the imbalance in the renewal of extracellular matrixtissue, such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontaldiseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency,atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPD), age-relatedmacular degeneration (ARMD) and cancer. MMP-inhibitor compounds are known. Most of these MMP-inhibitors are notsélective for a single MMP, such as those described by Montana and Baxter (2000) or byClark et al. (2000).

There is also a need in the prior art for novel inhibitors that are active on matrixmetalloprotease-13, in order to enrich the therapeutic arsenal that can be used for treatingpathologies associated with the destruction of the extracellular matrix and with cancer.

S

The patent application WO9826664 describes quinazolinone compounds which areused as new antifungic compounds.

The compounds of the présent application are novel and represent powerfuiinhibitors of MMP-13. They are consequentiy of use in the treatment of rheumatoidarthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel àisease,psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronicobstructive pulmonary diseases (COPDs), age-related degeneration (ARMD) and cancer.

SUMMARY OF THE INVENTION

The applicant has identified novel oxo azabicyclic compounds that are matrixmetalloprotease inhibitors, and more specifically compounds that are sélective MMP-13inhibitors.

More specifically, the présent invention relates to compounds of formula (I) : 012782 3

Ο wherein: • Xi, X2, and X3, independently of each other, represent a nitrogen atom or a group -CR3in which R3 represents a group selected from hydrogen, (Ci-C6)alkyl, amino, mono(Ci- 5 C6)alkylamino, di(Ci-C6)alkyIamino, hydroxy, (Ci-Cô)alkoxy, and halogen, wiîh the proviso that not more than two of the groups Xb X2 and X3 simultaneouslyrepresent a nitrogen atom, • G| represents a group selected from those of formulae (i/a) and (i/b): R4 R, R, n—é-r, (i/a) (i/b) 10 in which: - the carbon atom with number 2 is attached to the group N-Rj in the ring, R4 and R5, identical or different, independently of each other, represent a groupselected from hydrogen, (Ci-Cg)alkyl, aryl, aryl(C]-C6)alkyl, cycloalkyl,cycloalkyl(Ci-C6)alkyl, heteroaryl, heteroaryl(C]-C6)alkyl, heterocycloalkyl, and 15 heterocycloaIkyl(Ci-C6)alkyl, - Rô represents a group selected from : S hydrogen, trifluoromethyl, OR7, NR7R8, in which R7 and R8, identical ordifferent independently of each other, represent hydrogen or (Ci-Cô)alkyl, (Ci-Cô)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Cj-C6)alkyl,20 cycloalkyl(CrC&)alkyl, heteroaryl, heteroaryl(CrC5)alkyl, heterocycloalkyl, and heterocycloalkyl(Ci-C6)alkyl, these groups being optionally substituted by one ormore groups, which may be identical or different independently of each other,selected from halogen, amino, mono(Ci-C6)alkylamino, di(Ci-C6)alkylamino, eachalkyl moiety being identical or different independently of each other, cyano, 012782 4 trihalogeno(Ci-C6)alkyl, (CrC6)acyl, -C(=O)OR7, -0R7 and -SR7, in which R7 is asdefined hereinbefore, • G2 represents a group selected from carbon-carbon triple bond, -CH=C=CH-, C=O, C=S, S(O)ni in which ni represents an integer from 0 to 2 inclusive, and a group of 5 formula (i/c): Y, in which the carbon atom with number 1 is attached to the bicycle of the compound of formula (I), represents a group selected from oxygen, sulphur, -NH and -N(C]-C6)alkyl, .) and Y2 represents a group selected from oxygen, sulphur, -NH and -N(Ci-Cô)alkyl, 10 · n represents an integer from 0 to 6 inclusive, • Zi represents -CR9R10, wherein R9 and Rio, identical or different independently of eachother, represent a group selected from hydrogen, (Ci-Cfi)alkyl, trihalogeno(Ci-C6)alkyl,halogen, -OR7, -SR7, and -C(=O)OR7, in which R7 is as defined hereinbefore, amino,mono(C]-C6)alkylamino, di(Ci-C6)alkylamino in which each alkyl moiety is identical or 15 different independently of each other, and - wherein when n is greater than or equal to 2, the hydrocarbon chain Z] optionallycontains one to two isolated or conjugated multiple bonds, 1 -and/or wherein when n is greater than or equal to 2, one of said -CR9R10 may optionallybe replaced with a group selected from oxygen, S(O)„i in which ni is as defined 20 hereinbefore, -NH and -N(C]-C6)alkyl, • A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6-membered monocycle, 25 · Ri represents a group selected from : hydrogen, 012782 5 - (Ci-Cô)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, these groups may be optionallysubstituted with one or more groups, which may be identical or differentindependently of each other, selected ffom amino, cyano, trihalogeno(C|-C6)alkyl,cycloalkyl, -C(=O)NR7Rg, -C(=O)ORg, ORg, SRg, in which R7 and Rg, which may beidentical or different independently of each other, represent hydrogen or (CrC6)alkyl, - and the group of formula (i/d) :

(i/d) S in which p is an integer from 0 to 8 inclusive, S Z2 represents -CRnR]2 wherein Rn and R]2, identical or different independentlyof each other, represent a group selected from hydrogen, (Ci-C6)alkyl, phenyl,trihalogeno(Ci-C6)alkyl, halogen, amino, OR7, SR7 and -C(=O)OR7 in which R7represehts hydrogen or (Ct-C6)alkyl, and - wherein when p is greater than or equal to 2, the hÿdrocarbon chain Z2 optionallycontains one or two isolated or conjugated multiple bonds, - and/or wherein n is greater than or equal to 2, one of said -CRnRi2 may optionallybe replaced with a group selected from oxygen, S(O)„i in which ni is as defînedhereinbefore, -NH, -N(C|-C6)alkyl, and carbonyl, / B represents a group selected from aryl, heteroaryl, cycloalkyl, andheterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicyclecomposed of two 5- or 6- membered monocycle, ·/ q is an integer from 0 to 7 inclusive, Z the group(s) G3, which may be identical or different independently of each other,is (are) selected from (Ci-C6)alkyl, halogen, CN, NO2) CF3, OCF3, -(CH2)kNRi3Ri4,-N(R13)C(=O)Ri4, -N(Ri3)C(=O)OR14, -N(Ri3)SO2R,4, -N(SO2R13)2, -ORi3, -S(O)klRi3, -SOz-NÇRbXCH^^-NRmRis, -(CH2)kSO2NRl3Ri4, -X4(CH2)kC(=O)ORl3, -(CH2)kC(=O)OR13, -C(=O)O-(CH2)k2-NRi3R14, 012782 6 -C(=O)O-(CH2)k2-C(=O)OR16, -X4(CH2)kC(=O)NR13RI4, -(CH2)kC(=O)NRl3RI4,-Ri7-C(=O)ORi3, -X5-R|8j and -C(=O)-Ri9-NRi3R|4 in which : - X4 represents a group selected from oxygen atom, sulphur atom optionallysubstituted by one or two oxygen atoms, and nitrogen atom substituted by a 5 hydrogen atom or a (Ci-C6)alkyl group, - k is an integer from 0 to 3 inclusive, - kl is an integer from 0 to 2 inclusive, - k2 is an integer from 1 to 4 inclusive, - Rj3, R14 and R15, which may be identical or different independently of each 10 other, are selected from hydrogen and (Ci-C6)alkyl, - Riô represents a group selected from (Ci-C6)alkyl, -Ri9-NRi3Ri4,-Ri9-NRi3-C(=O)-Ri9-NRi4Ri5, and -C(=O)O-Ri9-NRi3Ri4 in which R19 representsa linear or branched (Ci-Cô)alkylene group, and R]3, Ri4 and R15 are as defïnedhereinbefore, 15 - R]7 represents a (C3-C6)cycloalkyl group, - X5 represents a group selected from single bond, -CH2-, oxygen atom, sulphuratom optionally substituted by one or two oxygen atoms, and nitrogen atomsubstituted by hydrogen atom or (C]-C6)alkyl group, - R!s represents a group selected from : 20 0 5- or 6-menbered monocycle aryl, heteroaryl, which is optionally substituted by one or more groups, which may be identical or different, selected from (CrCô)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C(=O)OR7 whereinR7 represents hydrogen or (C1 -C6)alkyl, 012782 7 o and 5- or 6-menbered monocycle cycloalkyl, heterocycloalkyl, which isoptionally substituted by one or more groupa, which may be identical ordifferent, selected from (Ct-C6)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl,amino, and -C(=O)OR7 wherein R7 represents hydrogen or (Ci-Cé)alkyl, • m is an integer from 0 to 7 inclusive, • the group(s) R2, which may be identical or different independently of each other, is(are) selected from (Ci-C6)alkyl, halogen, -CN, NO2, SCF3, -CF3, -OCF3, -NR7R8, -ORg, -SRg, -SORg, -SO2R8, -(CH2)kSO2NR7R8, -X7(CH2)kC(=O)OR8, -(CH2)kC(=O)OR8,-X7(CH2)kC(=O)NR7R8, -(CH2)kC(=O)NR7R8, and -X8-R20 in which: - X7 represents a group selected from oxygen, sulphur optionally substituted by one ortwo oxygen atoms, and nitrogen substituted by hydrogen or (C]-C6)alkyl, - k is an integer from 0 to 3 inclusive, - R7 and R8, which may be identical or different independently of each other, areselected from hydrogen and (Ci-C&)alkyl,

Xs represents a group selected from single bond, -CH2-, oxygen atom, sulphur atomoptionally substituted by one or two oxygen atoms, and nitrogen atom substituted byhydrogen atom or (Ci-Cô)alkyl group, - R2o represents 5- or 6-menbered monocycle aryl, heteroaryl, cycloalkyl, orheterocycloalkyl which is optionally substituted by one or more groups, which maybe identical or different, selected from (Ci-Ce)alkyl, halogen, hydroxy and amino,and when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selectedfrom nitrogen, oxygen and sulphur, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and thepharmaceutically acceptable salts thereof. 012782 8

According to a first embodiment, the invention relates to compounds of formula (I)wherein : • G2 represents a group selected from C=O, C=S, S(O)„i in which ni represents aninteger from 0 to 2 inclusive, or à group of formula (i/c):

Y 5 in which the carbon atom with number 1 is attached to the bicycle of the compound offormula (I), Y] represents a group selected from oxygen, sulphur, -ΝΉ and -N(Ci-C6)alkyl,and Y2 represents a group selected from oxygen, sulphur, -NH and -N(C]-C6)alkyl, • X], X2, X3, Gj, n, Zi, A, Ri(m andR2 are as defined in formula (I). 10 According to a second embodiment, the invention relates to compounds of formula (I)wherein : • G2 represents a carbon-carbon triple bond, • n represents an integer from 1 to 6 inclusive, • Xi, X2, X3, Gi, Zj, A, Rj, m and R2 are as defined hereinbefore. 15 According to a third embodiment, the invention relates to compounds of formula (I)wherein : • G2 represents a carbon-carbon triple bond, • n is zéro, • Zi is absent, 20 · A represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-menbered monocycle or bicycle composed of two 5- or 6- memberedmonocycle, • X], X2, X3, Gi, Rj, m and R2 are as defined hereinbefore.

According to a fourth embodiment, the invention relates to compounds of formula (I) 25 wherein : • G2 represents a carbon-carbon triple bond, • n is zéro, 012782 9 • Zi is absent, • A représente a phenyl group, • Ri represents a hydrogen atoni or a group of formula (i/d) :

<GA

S in which p is an integer from 0 to 8 inclusive, f "Li represents -CR] i Ri 2 wherein Ri i and R]2, identical or different independentlyof each other, represent a group selected from hydrogen, (Ci-C6)alkyl, phenyl,trihalogeno(Ci-C6)alkyl, halogen, amino, OR7, SR? and -C(=O)OR7 in which R7represents hydrogen or (Ci-C6)alkyl, and - wherein when p is greater than or equal to 2, the hydrocarbon chain Z2 optionallycontains one or two isolated or conjugated multiple bonds, - and/or wherein n is greater than or equal to 2, one of said -CRnRi2 may optionallybe replaced with a group selected from oxygen, S(O)ni in which ni is as defined hereinbefore, -NH, -N(Ci-Cô)alkyl, and carbonyl, S B represents a phenyl group, S q is an integer from 1 to 7 inclusive, S the group(s) G2, which may be identical or different independently of each other,is (are) selected from -(CH2)kNRi3Ri4, -N(R]3)C(=O)ORi4j -N(Ri3)SO2Ri4,-N(SO2R,3)2, -S(O)kIRi3, -SO2-N(R,3)-(^2)^^,4Rl5, -(CH2)kSO2NR,3Ri4,-X4(CH2)kC(=O)ORi3, -(CH2)kC(=O)OR,3, -Q^WCH^-NRuRm, -C(=O)O-(CH2)k2-C(=O)OR16, -X4(CH2)kC(=O)NR13Ri43 -(CH2)kC(=O)NR,3Ri4,-R,7-C(=Ô)OR,3, -X5-R18, -C(=O)-R,9-NR13Ri4 and -X6-R2) in which : - X) represents a group selected from oxygen atom, sulphur atom optionallysubstituted by one or two oxygen atoms, and nitrogen atom substituted by ahydrogen atom or a (Ci-C6)alkyl group, k is an integer from 0 to 3 inclusive,kl is an integer from 1 to 2 inclusive,k2 is an integer from 1 to 4 inclusive, - R,3, R,4 and R, 5, which may be identical or different independently of eachother, are selected from hydrogen and (Ci-C6)alkyl, 012782 10 - Riô représente a group selected from (Ci-C6)alkyl, -RI9-NRi3RI4,-Ri9-NRi3-C(=:O)-Rj9-NRj4R55J and —C(=O)O-Ri9-NRj3R]4 in which Ri9 representsa linear or branched (Ci-C6)alkylene group, and R13, Ri4 and R)5 are as definedhereinbefore, - Ri 7 represents a (C3-C6)cycloalkyl group, - X5 represents a group selected from single bond, -CH2-, oxygen atom, sulphuratom optionally substituted by one or two oxygen atoms, and nitrogen atomsubstituted by hydrogen atom or (Ci-C6)alkyl group, R]g represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl,these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or 6- membered monocycle, which is optionally substituted by one or more groups,which may be identical or different independently of each other, selected from(Ci-Cô)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C(=O)OR7wherein R7 represents hydrogen or (Ci-C6)alkyl, - Xû represents a group selected from -CH2-, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or(C|-C6)alkyl group, - R21 represents a phenyl group which is optionally substituted by one or more groups, which may be identical or different independently of each other, selectedfrom (Ci-Cô)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and -C(=O)OR7wherein R7 represents hydrogen or (Ci-Ce)alkyl, • and Xi, X2, X3, Gi,m and R2 are as defined in formula (I).

The substituent Rj that is preferred according to the invention is the group of formula (i/d):

(i/d) wherein Z2, p, B, G3 and q are as defined in the compound of formula (I).

More particularly, the substituent Ri that is preferred according to the invention is thegroup of formula (i/d):

(i/d) 012782 11 wherein Z2 représente a group -CRnRi2 in which Ru and Ri2 represents each a hydrogen'atom., and p, B, G3 and q are as defined in the compound of formula (I). 5 More particularly, the substituent Ri that is preferred according to the invention is thegroup of formula (i/d): wherein p is one, and Z2, B, G3 and q are as defined in the compound of formula (I).

More particularly, the substituent Rj that is preferred according to the invention is the10 group of formula (i/d) : (i/d> wherein B represents a phenyl group, q is equal.to 0 or 1, and G3, when it is présent,represents a group selected ffom OR13, halogen, S(O)kiRi3 and (CH2)kC(=O)ORi3 in whichRj3 represerîts an hydrogen atom or a (Ci-Cô)alkyl group, k is zéro, and kj is two, 15 and Z2, p are as defined in the compound of formula (I).

The invention relates also to the compounds of formula (I) wherein Gi represents a groupof formula (i/a) in which R4 represents a hydrogen atom or a methyl group, or a group offormula (i/b) in which Rj and R5, identical, represent each a hydrogen atom or a methylgroup, and Rg represents a hydrogen atom or a methyl group, and Xh X2, X3, G2, Zj, n, m 20 and R2 are as defined in formula (I).

Preferred compounds of the invention are compounds of formula (I) wherein Xi representsa group -CR3 in which R3 represents a hydrogen atom, X2 represents a nitrogen atom or agroup -CR3 in which R3 represents a hydrogen atom, and X3 represents a group -CR3 inwhich R3 represents a hydrogen atom. 012782 12

Other preferred compounds of the invention are compounds wherein G2 represents acarbon-carbon triple bond or a group of formula (i/c) in which Yi represents an oxygenatom, and Y2 represents a group -NH.

Still more preferred compounds of the invention are those compounds of formula (I)wherein Z] represents -CR9R10 in which R9 and Rio represent each a hydrogen atom, and nis one.

Especially preferred compounds of the invention are compounds wherein A represents agroup selected from phenyl and pyridyl, m is zéro or one, and R2 represents a(Ci-Cô)alkoxy group or a hydrogen atom.

More particularly, the invention relates to the following compounds of formula (I) : - 3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide 3-(4-methoxy-benzyl)-2-methyl-4-oxo-3,4-dihydro-quinazoline-6-carboxyIic acid 4-methoxy-benzylamide, hydrochloride 3-(4-methoxy-benzyl)-1 -methyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylicacid 4-methoxy-benzylamide 3- (4-methoxy-benzyl)-l,2,2-trimethyl-4-oxo-l,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide - 4-[6-(4-methoxy-benzylcarbamoyl)-4-oxo-l ,4-dihydro-2H-quinazolin-3-ylmethyf]-benzoic acid 4- [6-(4-methoxy-benzylcarbamoyl)-1 -methyl-4-oxo-1,4-dihydro-2H-quinazolin-3-ylmethylj-benzoic acid methyl ester 4-[6-(4-methoxy-benzylcarbamoyl)-l-methyl-4-oxo-l,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid, 3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 3-methoxy-benzylamide 3-(4-methanesulfonyl)-benzyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide 012782 13 - 4-Oxo-3-[4-(pyrrolidine-1 -sulfonyl)-benzyl]-3,4-dihydro-quinazoline-6-carboxylic acid4-methoxy-benzylamide - 4-[6-(3-methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid, - 3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide, - 3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]p)<rimidine-6-carboxylic acid 3-methoxy-benzylamide, - and 3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid4-methoxy-benzylamide

Further preferred compounds are: - 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide - 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide.

More particularly, the invention relates also to the following compounds of formula (I) : - 3-(4-fluorobenzyl)-6-(3-phenyl-prop-l-ynyl)-3 H-quinazolin-4-one, - methyl 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-477-quinazolin-3-ylmethyl]-benzoate, - 4-[4-oxo-6-(3-phenyl-prop-1 -ynyI)-47f-quinazolin-3-ylmethyl]-benzoic acid, - 3-(4-fluorobenzyl)-6-(3-phenyl-prop-1 -ynyl)-37f-pyrido[3,4-if]pyrimidin-4-one, - methyl 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-47/-pyrido[3,4-cQpyrimidin-3-ylmethyl]-benzoate, - 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-4//-pyrido[3,4-J]pyrimidîn-3-ylmethyl]-benzoicacid, _ 4-[4-oxo-6-(3-phenyl-prop-1 -ynyl)-4H-quinazoline-3-ylmethyl]-benzoic acid, _ 4-{6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazoline-3-ylmethyl}-benzoic acid, - 4-[4-oxo-6-(3-phenyl-prop-1 -ynyl)-4H-quinazoline-3-ylmethyl]-benzamide - and 3-[(3,5-difluoro-4-hydroxy)-benzyl]-6-(3-phenyl-prop-l-ynyî)-3H-quinazolin-4- one. 012782 14

Further preferred compounds are: - 4-[6-(3-Imidazol~l-yl-prop-l-ynyl)-4-oxo-4H-quinazolin-3-yîinethyl3-benzoic acid - 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzenesulfonamide - 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-qumazolin-3-ylmethyl]-benzonitrile 5 - 3-(3-Chloro-benzyl)-6-(4-phenyl-but-l-ynyl)-3H-quinazolin-4-one - 3-(3-Chloro-benzyl)-6-(3-phenyl-prop-l~ynyl)-3H-quinazolin-4-one - 4-[4-Oxo-6-(3-pyrazol-l-yl-prop-l-ynyl)-4H-quinazolin-3-yImethyl]-benzoic acid - 6-(3-PhenyI-prop-l-ynyl)-3-[4-(lH-tetrazol-5-yl)-benzyl]-3H-quinazolin-4-one - 3-(3,4-Difluoro-benzyl)-6-[3-(pyridin-4-yloxy)-prop-l-ynyl]-3H-quinazolin-4-one 10 - 3-(3,4-Difluoro-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-3H-quinazolin-4-one — N- {4- [4-Oxo-6-(3 -phenyl-prop-1 -ynyl)-4H-quinazolin-3 -ylmethyl] -phenyl} -acetami de - 3-(3,4-Difluoro-benzyl)-6-(3-phenyl-prop-l-ynyl)-3H-quinazolin-4-one - 3-(4-Acetyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-3H-quinazolin-4-one - 6-(3-PhenyI-prop-1 -ynyl)-3-pyridin-4-ylmethyl-3H-quinazolin-4-one 15 - 6-[3-(4-l\ïethoxy-phenyl)-prop-l-ynyl]-3-pyridin-4-ylmethyl-3H-qumazolm-4-one

Most preferred are the compounds listed in the table below, which refers to the exampleslater in the application.

Ex. 0 Methyl 4-[4-Oxo-6-(3- 9 U phenyl-prop-1 -ynyl)-4H- quinazolin-3-ylmethyl]' benzoate Ex. 0 4-[4-Oxo-6-(3-phenyl-prop- 10, 18 U ^k O 1 -ynyl)-4H-quinazolin-3-ylmethylj-benzoic acid Ex. 0 || 4-[6-(3-Methoxy- 17 MeCk II □ m. benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl]benzoic acid Ex. 0 4- {6-[3-(4-Methoxy-phenyl)- 19 1 ^k ΜγΟΗ prop-1 -ynyl]-4-oxo-4H- MeC) 1 quinazoline-3-ylmethyl} -benzoic acid 0 — 012782 15

Ex. 0 II 0 II 3-(3-Fluoro-benzyl)-4-oxo- 23 H oiny 3,4-dihydro-pyrido [3,4-d]pyrimidine-6 carboxylicacid 3-methoxy-benzylanxide Ex. 0 II 0 y 3-(3-Fluoro-benzyl)-4-oxo- 24 XX" MeO^A H A’ 3,4-dihydro-pyrido[3,4-d]pyrimidine-6 carboxylicacid 4-methoxy-benzylamide Ex. O 4-[6-(3-Imidazol-l-yl-prop- 58 NA A. Laa l-ynyl)-4-oxo-4H- (j j XLL-°h quinazolin-3-ylmethylj- N H O benzoic acid Ex. AA A O 4-[4-Oxo-6-(3-phenyl-prop- 59 U If yo/ 1 -ynyl)-4H-quinazolin-3-ylmethyl]- N S^ 0' NH2 benzenesulfonamide Ex. AA A 0 4-[4-Oxo-6-(3 -pheny 1-prop- 60 U ( A 1 -ynyl)-4H-quinazolin-3-ylmethylj-benzonitrile Ex. CIH O 6-(3-Phenyl-prop-1 -ynyl)-3- 64 CT Ά. [4-(lH-tetrazol-5-yl)- |f ^5γ ÿxv. benzyl] -3 H-quinazolin-4-one N—N H Ex. wA, 3-(3,4-Difluoro-benzyl)-6-[3- 65 X O (pyridin-4-yloxy)-prop-1 - c aLnAVf La J La ynyl]-3H-quinazolin-4-one • Ex. SS. O 3-(3,4-Difluoro-benzyl)-6-[3- 66 H,C. A3 0 A. Ά (4-methoxy-phenyl)-prop-1 -ynyl] -3 H-quinazolin-4-one Ex. 0 N- {4-[4-Oxo-6-(3-phenyl- 67 U j( Ά- A, H 3 prop-1 -ynyl)-4H-qumazolin-3-ylmethyl]-phenyl} -acetamide Ex. 0 3 -(4-Acetyl-benzyl)-6-[3 -(4- 69 H„C J! A A Ar nAA methoxy-phenyl)-prop-1 - 3 0 XA^1 Ϊ)γίΗ; 0 ynyl]-3H-quinazolin-4-one 012782 16

Ex. 70 6-(3-Phenyl-prop-1 -ynyl)-3- pyridin-4-ylmethyl-3H- quinazolin-4-one Ex. 71 "·%€Ρ*χύ·~Ο 6-[3-(4-Methoxy-phenyl)-prop-1 -ynyl]~3-pyridin-4-ylmethyI-3H-quinazolin-4-one

The optical isomers, the N-oxides, as well as the addition salts with a pharmaceutically-acceptable acid or base, of the preferred compounds form an intégral part of the invention. 5 The invention also relates to a pharmaceutical composition comprising as active ingrédientan effective amount of a compound of formula (I) together with one or morepharmaceutically-acceptable excipients or carriers.

Another embodiment of the invention concems the use of the compound of formula (I) forthe préparation of a médicinal product intended for treating a disease involving therapy by 10 inhibition of matrix metalloprotease, and more particulariy of type-13 matrixmetalloprotease.

The invention also relates to a method for treating a living body afflicted with a diseaseinvolving a therapy by inhibition of matrix metalloprotease, and more particulariy of type-13 matrix metalloprotease, the said method comprising the administration of an effective 15 amount of a compound of formula (I) to a patient in need thereof. A preferred method of treatment according to this invention is treatment of a diseaseselected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontaldiseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency,atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration 20 and cancers.

More particulariy, a preferred method of treatment according to this invention is treatmentof disease selected from arthritis, osteoarthritis and rheumatoid arthritis. 012782 17

DETAILED DESCRIPTION OF THE INVENTION

The compounds provided by this invention are those defined in formula (I). In formula (I),it i s understood that : - a (Ci-Cô)alkyl group dénotés a linear or branched group containing from 1 to 65 carbon atoms ; example of such groups, without implying any limitation are methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl, - a (C2-Cô)alkenyl group dénotés a linear or branched group containing from 2 to 6carbon atoms, and one or more double bonds ; examples of such groups without implyingany limitation are vinyl, allyl, 3-buten-l-yl, 2-methyl-buten-l-yl, hexenyl, 10 - a (C2-C6)alkynyl group dénotés a linear or branched group containing from 2 to 6 carbon atoms, and one or more triple bonds ; examples of such groups without implyingany limitation are ethynyl, propynyl, 3-butyn-l-yl, 2-methyl-butyn-l-yl, hexynyl, - a (Ci-Cô)alkoxy group means the alkyl group as mentioned above bound through anoxygen atom'; e-xamples of such compounds without implying any limitation are methoxy, 15 ethoxy, π-propyloxy, Zert-butyloxy, - a mono(Ci-C6)alkylamino dénotés a amino group substituted by one (Ci-C6)alkylgroup as defined hereinbefore ; example of such groups, without implying any limitationare methyl amino, isobutyl amino, ethylamino, - a di(Ci-C6)alkylamino dénotés a amino group substituted by two (Ci-Cg)alkyl2u groups as defined hereinbefore, each alkyl group being identical or different ; example of such groups, without implying any limitation are dimethylamino, diethylamino, an aryl group dénotés an aromatic monocyclic or bicyclic System containing from 5 to 10 carbon atoms, and in the case of a bicyclic System, one of the ring of which isaromatic in character, and the other ring of which may be aromatic or partially 25 hydrogenated ; examples of such groups without implying . any limitation are, phenyl,naphthyl, indenyl, benzocyclobutenyl, a heteroaryl group dénotés an aryl group as described above in which 1 to 4 carbonatoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen ;examples of such groups without implying any limitation are furyl, thienyl, pyrrolyl, 30 pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, 012782 18 isoquinolyl, benzodioxolyl, benzodioxinyl, benzo[l,2,5]thiadiazolyl,benzo[l ,2,5]oxadiazolyl, - a cycloalkyl group dénotés a monocyclic or bicyclic system containing from 3 to 10carbon atoms, this system being saturated or partially unsaturated but without aromaticcharacter ; ex amples of such groups without implying any limitation are cyclopropyl,cycîobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl,norbomyl, - a heterocycloalkyl group dénotés a cycloalkyl group as defined hereinbefore inwhich 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen,sulfur, and nitrogen, - a bicycle dénotés two fused-monocycle and, - a trihalogeno(Ci-C6)alkyl group dénotés an alkyl group as defined above whichcontains a trihalogeno group ; examples of such groups without implying any limitation aretrifluoromethyl, 2,2,2-trifluoroethyl, - a (Ci-C7)acyl group dénotés an alkyl group or a aryl group as defined above boundîhrough a carbonyl group ; examples of such groups without implying any limitation areacetyl, ethylcarbonyl, benzoyl, - a multiple bond dénotés double bond or triple bond, - a halogen atom means fluoro, chloro, bromo or iodo, - optical isomers refer to racemates, enantiomers and diastereoisomers.

The invention also relates to the pharmaceutically acceptable salts of the compounds offormula (I). A review of the pharmaceutically acceptable salts will be found in J. Pharm.Sci., 1971,66,1-19.

Pharmaceutically acceptable acids mean non-toxic salts derived from minerai or organicacids. Among those there may be mentioned, without implying any limitation,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, nitric acid, citric acid,acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid,glutaric acid, fumaric acid, tartaric acid, rnaleic acid, ascorbic acid, oxalic acid,methanesulfonic acid, camphoric acid, benzoic acid, toluenesulfonic acid, etc...Pharmaceutically acceptable bases mean non-toxic salts derived from minerai or organicbases. Among those, there may be mentioned, without implying any limitation, sodium 012782 19 hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, tert-butylamine,dibenzylethylenediamine, piperidine, pyrrolidine, benzylamine, quatemary ammoniumhydroxides etc...

The invention also relates to a process for the préparation of compounds of formula (I),which uses as starting material a compound of formula (Π):

in which Xj, X2, X3, and Y1 hâve the same définitions as the compound of formula (I), andT represents a group (Ci-Cô)alkyl, compound of formula (II) which is treated with a compound of formula (III): in which Zi, Y2, R2, A, n and m hâve the same définitions as the compound of formula (I), by activating the acid function with an activator, in the presence of diisopropylethylamineand a solvent, to yield the compound of formula (IV) : 15

in which Xt, X2, X3, Yi, T, Zi, Y2, R2, A, n and m are as defined hereinbefore, compound of formula (IV) in which the ester group is hydrolyzed and the subsequentlycompound obtained is then treated with an activator in the presence of a base and a primaryamine with the general formula Rt-NH2 in which Ri is as defined in the compound of 20 formula (I), to yield the compound of formula (V) : 012782 20

in which Xb X2, X3, Y,, Y2, Zb R2, Rb A, n and m are as defîned hereinbefore, which compound of formula (V) is treated·: • either with triethyl orthoformate under heating condition, to yield the compound offormula (I/a), which is a particular case of the compound of formula (I): 10 15

in which Xb X2, X3, Yb Y2, Zb R2, Rb A, n and m are as defïned hereinbefore, • or under heating condition in the presence of acid, with a compound of formula (VI): W (V,

O O in which R4 has the same définition as the compound of formula (I), to yield the compound of formula (I/b), which is a particular case of the compound offormula (I): 1

(I/b) in which Xb X2, X3, Yb Y2, Zb R2, Rb R4, A, n and m are as defîned hereinbefore, • or with a compound of formula (VII) in basic condition:

O (VU) in which R4 and R5 hâve the same définition as the compound of formula (I), 012782 21 to yield the compound of formula (IZc), which is a particular case of the compound offormula (I):

in which Xj, X2, X-i, Y), Y2, Zj, R2, Ri, R4, Rs, A, n and m are as defined hereinbefore, which compound of formula (I/c) is optionally treated with a hydride, in the presence of acompound of formula (VIH): 10 R6-Hal (VIII) in which has the same définition as the compound of formula (I), to yield the compound of formula (I/d), which is a particular case of the compound offormula (I): *

in which Xj, X2, X3, Yi, Y2, Zj, R2, Ri, R», Rs, Rô, A, n and m are as defined hereinbefore, compounds of formulae (I/a), (I/b), (I/c) and (I/d) constitute some compounds of theinvention, which are purified, where appropriate, according to a conventional purification 15 technique, which are separated, where appropriate, into their different isomers according toa conventional séparation technique, and which are converted, where appropriate, intoaddition salts thereof with a pharmaceuticaîly-acceptable acid or base, or into N-oxidethereof.

The invention also relates to a process for the préparation of compounds of formula (I), 20 which uses as starting material a compound of formula (X): 012782 22

Ο in which Xj, X2, and X3 hâve the same définitions as the compound of formula (I), and Halrepresents a halogen atom, which compound of formula (X) is treated in a first step with a derivate of phosgene to5 yield the compound of formula (XI):

in which Xi, X2, X3 and Hal are as defined hereinbefore, which compqund of formula (XI) is treated in basic medium with a primary amine ofgeneral formula Ri-NH2 in which Ri has the same définition as in the compound of 10 formula (I), to yield the compound of formula (XII):

O in which Xj, X2, X3, Ri and Hal are as defined hereinbefore, which compound of formula (XII) is treated: • either with triethyl orthoformate under heating condition, to yield the compound offormula (ΧΠΙ/a) : X.

/Âx/N

X

(XlII/a)

Hal 15

O 012782 23 in which Xj, X2, X3» Ri and Hal are as defined hereinbefore, • or under heating condition in the presence of an acid, with a compound of formula(VI):

O O in which has the same définition as the compound of formula (I),to yield the compound of formula (ΧΙΙΙ/b) :

in which Xj, X2, X3, Hal, Rt and R4 are as defined hereinbefore, or with a compound of formula (VII) in basic conditions: R,

Rc (VII) 10 in which R4 and R5 hâve the same définition as the compound of formula (I), to yield the compound of formula (ΧΙΠ/c) :

(XIII/c) in which Xi, X2, X3, Hal, Rj, R» and R5 are as defined hereinbefore, 15 which compound of formula (XIII/c) is optionally treated with a hydride, in the presence ofa compound of formula (VIII):

Rg-Hal (VIII) in which Rô has the same définition as the compound of formula (I), and Hal is a halogenatom, 012782 24 to yield the compound of formula (XIII/d), which is a particular case of the compound offormula (I):

(XIII/d) iil which Xb X2, X3, Hal, Rb R4, R5 and R^ are as defined hereinbefore, ail compounds of formulae (XlII/a), (ΧΙΠ/b), (XIII/c) and (XIII/d) constitute thecompound of formula (XlII/e):

(XIII/e) in which Xi, X2, X3, Hal, R] and Gj are as defined in the compound of formula (I), 10 compound of formula (XIII/e) which is treated under conditions of palladium-catalyzedalkynylation with a compound of formula (XIV):

SnBu, (XIV) in which Zj, R2, A, n and m hâve the same définitions as the compound of formula (I), to yield the compound of formula (I/e), which is a particular case of the compound offormula (I):

in which X|, X2, X3, R|, Gi, Zb R2, A, n and m hâve the same définitions as the compoundof formula (I), 15 012782 25 compounds of formula (I/e) constitute some compounds of the invention, which arepurified, where appropriate, according to a conventional purification technique, which areseparated, where appropriate, into their different isomers according to a conventionalséparation technique, and which are converted, where appropriate, into addition salts 5 thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.

An alternative way to obtain the compound of formula (ΧΙΙΙ/a) from compound of formula(XI) is described in the following scheme 1 : 10

Scheme 1

R,-Haï

Cs2CO3, DMF

(ΧΙΙΙ/a) O 15

Wherein Xb X2, X3, Ri and Hal, are as defined above.

In a first step, compound of formula (XI) is treated with an aqueous solution of ammoniumhydroxide to yield compound of formula (ΧΙ/a) which is reacted with triethyl orthoformatein the presence of a catalytic amount of acid like ραζ-α-toluene sulfonic acid (PTSA). The37/-quinazolin-4-one (ΧΙ/b) obtained is condensed in basic medium to a compound offormula R|-Hal, in which Ri is as defined in the compound of formula (I) and Halrepresents a halogen, to yield the compound of formula (XlII/a). 20 The invention also relates to a process for the préparation of compounds of formula (I),which uses as starting material a compound of formula (ΧΙΙΙ/e) : 012782 26

(ΧΙΠ/e) in which Xj, X2, X3, Ri and Gf are as defined in the compound of formula (I), and Hal is ahalogen atom, compound of formula (ΧΙΙΙ/e) which is condensed, in the presence of5 dichlorobis(triphenylphosphine)palladium, cupper iodide and jV.A'-diisopropylethylamine in dimethylfonnamide, on a compound of formula (XV) : (XV) in which Z], R2, A, n and m hâve the same définitions as the compound of formula (I), 10 to yield the compound of formula (I/e), which is a particular case of the compound offormula (I):

in which Xi, X2, X3, Ri, Gj, Zj, R2, A, n and m hâve the same définitions as the compoundof formula (I).

The invention also relates to a process for the préparation of compounds of formula (I),which uses as starting material a compound of formula (ΧΠΙ/e) :

in which Xi, X2, X3, Ri and Gj are as defined in the compound of formula (I), and Hal, is ahalogen atom, 15 012782 27 compound of formula (ΧΙΙΙ/e) which is reacted with carbon monoxide in an alkalinemedium in the presence of a protic solvent like methanol and a catalytic amount ofpalladium ,· to yield the compound of formula (XVI):

(XVI) in which Xb X2, X3, Ri and Gi are as defined in the compound of formula (I), compound of formula (XVI) which is hydrolysed under basic medium to yield thecompound of formula (XVII):

10 in which X], X2, X3, R] and G] are as defined in the compound of formula (I), compound of formula (XVII) which is condensed under basic.medium in the presence of aMukayama reagent, on the compound of formula (XVIII): (xvm) 13 in which Z], R2, A, n and m hâve the same définitions as the compound of formula (I£ to yield the compound of formula (I/f), which is a particular case of the compound of formula (I):

(I/f) in which Xb X2, X3, Zb R2, Rb A, n and m are as defined hereinbefore, compounds of formula (I/f) constitute some compounds of the invention, which arepurified, where appropriate, according to a conventional purification technique, which areseparated, where appropriate, into their different isomers according to a conventional 20 012782 28 séparation technique, and which are converted, where appropriate, into addition saltsthereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.

The invention also relates to a process for the préparation of compounds of formula (I),which uses as starting material a compound of formula (XIX) :

in which Hal represents a halogen atom, 10 compound of formula (XIX) which is heated in the presence of formamidine acetate in apolar solvent like 2-methoxyethan-l-ol, to yield the compound of formula (XX):

(XX) in which Halis as defîned hereinbefore, compound of formula (XX) which is treated in basic medium with a compound of formula15 Ri-Hal, in which Ri is as defmed in the compound of formula (I) and Hal represents a halogen atom, to yield the compound of formula (XXI):

in which Hal and Ri are as defîned hereinbefore, 20 compound of formula (XXI) which is reacted with carbon monoxide under basic mediumin the presence of an alcoholic solvent like methanol and a catalytic amount of palladiumlike PdChidppf) , to yield the compound of formula (XXII): 012782 29

compound of formula (XXII) which is condensed, in the presence of trimethylaluminium,5 with a compound of formula (XVIII): WAr (XVIII) in which Zj, R2, A, n and m hâve the same définitions as the compound of formula (I), 10 to yield the compound of formula (I/g), which is a particular case of the compound offormula (I):

15 in which Z|, R2, Ri, A, n and m are as defined hereinbefore, compounds of formula (I/g) constitute some compounds of the invention, which arepurified, where appropriate, according to a conventional purification technique, which areseparated, where appropriate, into their different isomers according to a conventionalséparation technique, and which are converted, where appropriate, into addition salisthereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.

The compounds of the invention that are présent in the form of a mixture of20 diastereoisomers are isolated in a pure form by using conventional séparation techniques such as chromatography.

As mentioned above, compounds of formula (I) of the présent invention are matrixmetalloprotease inhibitors, and more particularly inhibitors of the enzyme MMP-13. 012782 30

In this respect, their use is recommended for the treatment of diseases or complaintsinvolving a therapy by MMP-13 inhibition. By way of example, the use of the compoundsof the présent invention may be recommended for the treatment of any pathology in whichdestruction of extraceîlular matrix tissue occurs, and most particularly pathologies such asarthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases,inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency,atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related maculardegeneration and cancers.

The présent invention also relates to pharmaceutical compositions comprising as activeingrédient at least one compound of formula (I), an isomer thereof, a N-oxide thereof, or anaddition sait thereof with a pharmaceutically-acceptable acid or base, alone or incombination with one or more pharmaceutically-acceptable, inert, non-toxic excipients orcarriers.

Among the pharmaceutical compositions according to the invention, there may bementioned more especially those that are suitable for oral, parentéral (intravenous,intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal,perlingual, buccal, ocular or respiratory administration.

Pharmaceutical compositions according to the invention for parentéral injections especiallyinclude aqueous and non-aqueous stérile solutions, dispersions, suspension and émulsions,and also stérile powders for reconstituting injectable solutions or dispersions.

Pharmaceutical compositions according to the invention for oral administration in solidform especially include tablets or dragées, sublingual tablets, sachets, gelatin capsules andgranules, for oral, nasal, buccal or ocular administration in liquid form, especially includeémulsions, solutions, suspensions, drop, syrups and aérosols.

Pharmaceutical compositions for rectal or vaginal administration are preferablysuppositories, and those for per- or trans-cutaneous administration especially includepowders, aérosols, creams, ointment, gels and patches. 012782 31

The pharmaceutical compositions mentioned hereinbéfore illustrate the invention but donot limit it in any way.

Among the pharmaceuticaily acceptable, inert, non-toxic excipients or carriers there maybe mentioned, by way of non-limiting example, diluents, solvents, preservatives, wettingagents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents,retardants, lubricants, absorbents, suspending agents, colourants, aromatizing agents etc...

The useful dosage varies according to the âge and weight of the patient, the administrationroute, the pharmaceutical composition used, the nature and severity of the disorder and theadministration of any associated treatments. The dosage ranges from 2 mg to 1 g per day inone or more administrations. The compositions are prepared by methods that are commonto those skilled in the art and generally comprise 0.5% to 60% by weight of activeprinciple (compound of formula (I)) and 40% to 99.5% by weight of pharmaceuticailyacceptable excipients or carriers.

The examples that follow illustrate the invention but do not limit it in any way.

The starting materials used are products that are known or that are prepared according toknown operating procedures. The various préparations yield synthetic intermediates thatare useful in préparation of the compounds of the invention. Some of these intermediatesare new compounds.

The structures of the compounds described in the Examples and Préparations weredetermined according to the usual spectrophotometric techniques (infrared, nuclearmagnetic résonance, mass spectrometry,...)

In the Préparations and Examples, it is understood that : - DMF means Dimethylformamide, - THF means tetrahydrofurane, - DMSO means dimethylsulfoxide, 012782 32 - TOTU means O-(ethoxycarbonyl)cyanomethylamino]-AUV’-//'-A -tetramethyluranium fluoroborate, DIPEA means diisopropylethylamine.

EXAMPLES

Préparation 1 : 4-Amino-3-[(4-methoxy)-benzyIcarbamoyl]-l-carboxylic acid 4-methoxy-benzylamide

Step 1: 4-Àmino-isophthalic acid 6.3 g (150 mmol) of L1OH.H2O are added to a stirred solution of 15.7 g (75 mmol) ofmethyl 4-amino-isophtalate in 300 ml of dioxane and 1200 ml of water. The reactionmixture is heated for 1 hour to 100°C, cooled and acidifîed to pH=T by the addition ofconcentrated HCl. A precipitate is obtained then filtered off, washed, and dried undervacuum to yiqld 13 g (yield = 95.7%) of the desired compound. N.M.R (DMSO-40 ’H Ô (ppm ) : 6.80 (d,lH); 6.80-7.80 (bs); 7.80 (dd,lH); 8.35 (s,lH);11.9-13.1 (bs)

Step 2 : 4-Amino-3-[(4-methoxy)-benzylcarbainoyl]-phenyl-l-carboxylic acid 4-methoxy-benzylamide

2.25 g (16.5 mmol) of 4-methoxybenzylamine, 5.4 g (16.5 mmol) of TOTU and 5.4 ml (3.9g, 30 mmol) of DEPEA are added successively to a stirred solution of 2.7 g (15 mmol) ofthe compound obtained in Step 1 to 100 ml of DMF. The reaction mixture is stirredovemight at room température, then the solvent is removed under vacuum. The crudemixture is taken up in dichloromethane, and washed successively with HCl IN and NaOHIN. After séparation by décantation the organic phase is dried over Na2SO4 andconcentrated under vacuum. The crude product is purified by chromatography andconcretized from a mixture of dichloromethane and ether to yield 3.1 g (yield=49.3%) ofthe desired compound. 012782 33 N.M.R (DMSO-Jd) 'H δ (ppm) : 3.70 (s,6H); 4.35 (t,4H) ; 6.70 (d,lH); 6.80-6.90(m,6H) ; 7.20-7.30 (m,4H) ; 7.65 (dd,lH) ; 8.10 (s,lH) ; 8.45 (t,lH) ; 8.75 (t,lH)

Préparation 2 : Methyl 4-{[2-Amino-5-(4-methoxy-benzylcarbamoyI)-benzoylamino]-methylj-benzoate 5 Step 1 : Methyl 6-Amino-N~(4-niethoxy-benzyl)-isophthalate

6.56 g (20 mmol) of TOTU and 2.6 ml (2.74 g, 20 mmol) of 4- methoxybenzylamine areadded to a stirred solution of 4.2 g (18.1 mmol) of 4-amino-3-methylcarboxylate-l-phenylcarboxylic acid in 150 ml of anhydrous DMF. The mixture is cooled at 0°C and 9.5 ml 10 (7.02 g, 54.3 mmol) of DIPEA are added. The reaction mixture is stirred ovemight at room température \and concentrated under vacuum. The residue is taken up in 150 ml ofdichloromethane, washed with 100ml of a saturated solution of NaHCCh. The organiclayer is dried and concentrated under vacuum. After a chromatography over silica gel 3.5 g(yield=62%) of the desired compound are isolated. 15 TLC : CH2Cl2/MeOH 90/10 Rf= 0.80 N.M.R (DMSO-ifc) ’H δ (ppm) : 3.80 (s,3H) ; 3.90 (s,3H) ; 4.55 (d,2H) ; 6.0-6.15 (bs,2H) ;6.15-6.30 (bs,lH) ; 6.65 (d,lH) ; 6.90 (d,lH) ; 7.25-7.30 (m,2H) ; 7.80 (d,lH) ; 8.25(s,lH).- PURITY : HPLC = 98.5% 20 Step 2: 6-Amino-N-(4-methoxy-benzyl)-isophthalainic acid

0.3 g (7 mmol) of LiOH, H2O is added to a stirred solution of 1.1 g (3.5 mmol) of thecompound obtained in the preceding Step 2 in 10 ml of dioxane and 40 ml of water. Thereaction mixture is heated under reflux for 2 hours, cooled, and acidified at pH=l by 012782 34 addition of concentrated HCL The precipitate obtained is filtered off and dried to give thedesired compound. N.M.R (DMSO-Jd) 'H δ (ppm) : 3.70 (s,3H) ; 4.35 (d,2H) ; 6.75 (d,lH) ; 6.85 (d,2H) ; 7.20(d,2H) ; 7.75 (dd,lH) ; 8.30 (slH) ; 8.65 (t,lH). 5 Step 3 : Methyl 4-{[2-Amino-5-(4-methoxy-benzylcarbamoyl)-beitzoylainino]-inethyl}-benzoate

The desired compound is obtained according to the procedure described in the Step 1 ofPréparation 2 using as starting material the compound obtained in the preceding step 2 and 10 as reactant the methyl 4-(aminomethyl)benzoate hydrochloride. It is puriiied bychromatography over silica gel using a mixture of dichloromethane/ether as eluant.

S N.M.R (DMSO-ûftf) 'H δ (ppm) : 3.70 (s,3H) ;3.85 (s,3H) ; 4.40 (d,2H) ; 4.50 (d,2H) ; 6.70(d,lH) ; 6.80-6.90 (m,4H) ; 7.25 (d,2H) ; 7.45 (d,2H) ; 7.70 (dd,lH) ; 7.95 (d,2H) ; 8.15(s,lH) ; 8.45 (t,lH) ; 8.90 (t,lH). 15 Préparation 3 : 3-(4-fluorobenzyl)-6-iodo-3H-quinazoIin-4-one

Step 1 : b-iodo-lH-benzo[a][l,3]oxazine-2,4-dione

To a suspension of 2-amino-5-iodobenzoic acid (4.9 g, 18.0 mmol) in H2O (20 ml) andconcentrated HCl (5 ml) is added dioxane (50 ml) until a clear solution is obtained. Neat 20 diphosgene (5.95 g, 30.0 mmol) is added dropwise (with cooling at times so that thesolution would not boil) to give a white precipitate. Aller stirring at room température for10 min., H2O (ca. 100 ml) is added and the precipitate is filtered and washed with copiousamount of H2O. It is dried in vacuo to give the desired product (5.2 g, quantitative) aswhite crystals. 012782 35 N.M.R (DMSO-7d) ‘H δ (ppm) : 6.93 (d, J= 8.6 Hz, 1H), 8.00 (dd, J = 8.6, 2.0 Hz, 1H),8.10(d, 7=2.0 Hz,1H), 11.8 (s, 1H); MS (APCI), M/z 288.0 (Μ - 1).

Step 2 : 2-aitiino-N-(4-fluorobenzyl)-5-iodo-benzamide

10 15

To a 50°C solution of the compound obtained in the preceding Step 1(2.1 g, 7.27 mmol) inDMF (20 ml) are added neat 4-fluorobenzylamine (1.18 g, 9.45 mmol) dropwise. Thereaction is stirred at room température for 10 min. while bubbling is observed (CO2), andTLC indicated the completion of the reaction. The reaction content is poured into aseparatory formel charged with CH2CI2 and H2O. After séparation, the organic layer iswashed with H2Û(3x50 ml) and brine (50 ml). It is dried (Na2SÛ4), filtered andconcentrated in vacuo to give a white solid which is purified using flash chromatography togive the desired compound as a white solid (2.5 g, 93%). N.M.R (DMSO-7tf) 'H δ (ppm) : 5.15 (d, J= 5.8 Hz, 2H), 6.50 (s, 1H), 7.03 (m, 1H); 7.34(m, 1H), 7.43 (d,7= 8.5 Hz, 1H), 8.02 (m, 1H), 8.10 (s, 1H), 8.66 (d,y = 1.9 Hz, 1H), 9.18(t, 7= 5.8 Hz, 1H); MS (APCI), M/z 371.0 (M + 1).

Step 3 :3-(4-fluorobenzyl)-6-iodo-3H-qiiinazolin-4-one

20

To the solution of the compound obtained in the preceding Step 2 (2.69 g, 7.27 mmol) intriethyl orthoformate is added catalytic amount of TsOH. The solution is refluxed for 5h,cooled to room température. After removal of ail volatiles in vacuo, the residue is purifiedusing flash chromatography to give the desired quinazolinone as a brownish solid.Trituration then afforded the desired compound as a white solid (1.56 g, 58%). N.M.R (DMSO-<4) 'H δ (ppm) : 5.15 (s, 2H), 7.03 (m, 1H); 7.34 (m, 1H), 7.43 (d, 7= 8.5Hz, 1H), 8.02 (m, 1H), 8.10 (s, 1H), 8.66 (d, 7= 1.9 Hz, 1H); 25 012782 36 MS (APCI), M/z 381.0 (M + 1).

Préparation 4 : Methyl 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyI)-benzoate

Step 1; Methyl 4-[(2-Amino-5-iodo-benzoylainino)-methylJ-benzoate

O

5 To a 50°C solution of the compound obtained in the Step 1 of Préparation 3 (1.4 g, 4.84mmol) in DMF (20 ml) is added the hydrochloride sait of 4-carbomethoxy-benzylamine(1.17 g, 5.8 mmol). The reaction is stirred at room température for 1 h while bubbling isobserved (CO?), and TLC indicated the completion of the reaction. The reaction content ispoured into a separatory funnel charged with CH2CI2 and H2O. After séparation, the 10 organic layer is washed with H2O three times to remove DMF. It is then washed withbrine, dried (h^SCh), filtered and concentrated in vacuo to give the desired amide as abrown solid (2.0 g, quantitative). N.M.R (DMSO-i/d) ’H Ô (ppm) : 3.31 (s, 3H), 4.36 (d, 7= 5.9 Hz, 2H), 6.55 (d, 7= 8.6 Hz,1H), 6.59 (s, 2H), 7.15 (m, 2H), 7.35 (m, 4H), 7.80 (d, 7= 1.9 Hz, IH), 8.88 (t, 7= 5.9 Hz, 15 1H); MS (APCI), M/z 411.0 (M + 1).

Step 2 : Methyl 4-(6-Iodo-4-oxo-4H-quinazolin-3-yhnethyl)-benzoate

O

To a solution of the compound obtained in the preceding Step 1 (2.0 g, 4.84 mmol) in20 triethyl orthoformate is added catalytic amount of TsOH. The solution is refluxed for 5h,cooled to room température. After removal of ail volatile solvents in vacuo, the residue ispurified using flash chromatography to give the desired quinazolinone as a brownish solid.

Trituration then afforded the desired compound as a white solid (1.0 g, 50%). N.M.R (CDCb) ’H δ (ppm) 3.31 (s, 3H), 5.26 (d, 2H), 7.48 (m, 4 H), 7.90 (d, 7= 6.8 Hz, .25 2H),8.10(m, 1H), 8.40 (d, 7= 1.7 Hz, 1H), 8.60 (d, 7= 1.5 Hz, 1H) . 012782 37 MS (APCI), M/z 421.3 (M + 1).

Préparation 5 :3-(4-Fluoro-benzyl)-6-iodo-3H-pyrido[3,4-d]pyrimidin-4-one

Step 1: 6-Iodo-lH-pyrido[3,4-d][l,3]oxazine-2,4-dioneO

O

H 5 To a suspension of 2-amino-5-iodo-isonicotinic acid (18.0 mmol) in H2O (20 ml) andconcentrated HCl (5 ml) is added dioxane (50 ml) until a clear solution is obtained. Neatdiphosgene (5.95 g, 30.0 mmol) is added dropwise (with cooling at times so that thesolution does not boil) until a precipitate formed. After stirring at room température for10 minutes, H2O (100 ml) is added, and the precipitate is filtered and washed with a 10 copious amount of H2O. The filter cake is dried in vacuo to give the desired compound.

Step 2: 5-Ainiiio-N-(4-/luoro-benzyl)-2-iodo-isonicotinaniide

• To a 50°C solution of a compound obtained in Step 1 (7.27 mmol) in DMF (20 ml) isadded 4-fluorobenzylamine (9.45 mmol) dropwise. The reaction is stirred at room 15 température for 10 minutes while bubbling is observed (CO2), and TLC indicatescompletion of the reaction. The reaction content is poured into a separatory funnel chargedwith CH2CI2 and H2O. After séparation, the organic layer is washed with H2O (3x50 ml)and brine (50 ml). The organic layers are then dried (Na2SC>4), filtered and concentrated invacuo, and the residue optionally is purified using flash chromatography on silica gel to 20 give the desired compound. 012782 38

Step 3:3-(4-Fluoro-benzyl)-6-iodo-3H-pyrido[3,4-d]pyrimidin-4-ojie

Το a solution of the compound obtained in Step 2 (7.27 mmol) in triethyl orthoformate isadded a catalytic amount ofpm'u-toluenesulfonic acid. The solution is refluxed for 5 hours,and cooled to room température. After removal of ail volatiles in vacuo, the residue ispurified using flash chromatography on silica gel to give the desired compound.

Préparation 6 : Methyl 4-(6-Iodo-4-oxo-47/-pyrido[3,4-i/]pyriinidin-3-ylinethyl)-benzoate

Step 1 : Methyl 4-{[(5-Amino-2-iodo-pyridine-4-carbonyl)-amino]-tnethyl}-benzoate 10

15

To a 50°C solution of the compound obtained in the Step 1 of Préparation 6 (4.84 mmol),in DMF (20 ml) is added the hydrochloride sait of 4-carbomethoxy-benzylamine (1.17 g,5.8 mmol). The reaction is stirred at room température for 1 hour while bubbling isobserved (CO2 évolution), and TLC indicates the completion of the reaction. The reactioncontent is poured into a separatory tunnel charged with CH2CI2 and H2O. After séparationof the layers, the organic layer is washed with H2O three times to remove DMF. Theorganic layer is then washed with brine, dried (Na2SC>4), filtered, and concentrated invacuo to give the desired compound.

Step 2 : Methyl 4-(6-Iodo-4-oxo-4H-pyrido[3,4-d]pyrimidin-3-ylmethyl)-benzoateO

To a solution of the compound obtained in Step 1 (4.84 mmol) in triethylorthoformate is added a catalytic amount of TsOH. The solution is refluxed for 5 hours, 20 012782 39 and cooled to room température. After removal of ail volatile solvents in vacuole residueis purified using flash chromatography on silica gel to give the desired compound.

Préparation 7 :3-(4-Fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 5

Step 1: Methyl 3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylate

2.0 g (5.27 mmoî) of the compound prepared from préparation 3, is dissolved in 50 ml of1:1 DMF:Methanol, an excess amount of triethylamine, and a catalytic amount of 10 Pd(dppf)Cl2· The reaction solution is poured into an autoclave and heated at 100°C for 4hours under carbon monoxide atmosphère. The reaction is cooled to room température andfiltered. The filtrate is concentrated in vacuo and the residue purified on a silica gel columnusing 1:1 Hex:EtOAc to yield the desired product as a white solid (100%). 15 Step2:3-(4-Fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid

1.7g (5.27 mmol) of the compound obtained in the preceding Step 1 is dissolved in 50 mlof 90%-THF: 10% Water. 10 équivalents of LiOH is added, and the reaction solution isrefluxed for 5 hours. The reaction solution is diluted with 100 ml of water, and 20 concentrated HCl is used to acidify the solution pH to 1.0. The solution is extracted with200 ml of EtOAc, and the organic layer is washed with 2x100 ml of water and 1x100 ml ofbrine. The organic layer is dried over MgSÛ4 and concentrated to yield 1.5 g of the desiredproduct as an off-white solid. 25 012782 40

Préparation 8 : 3-(4-Methanesulfonyl-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid

The compound is obtained according to the procedure described in Préparation 7 but using5 in Step 1 the compound obtained in Préparation 3 in which 4-methanesulfonyl- benzylamine is used in place of 4-fluorobenzylamine in the Step 2.

Préparation 9 : 3-[4-(Pyrrolidine-l-sulfonyl)-benzyI]-4-oxo-3,4-dihydro-quinazoIine-6-carboxylic acid

The compound is obtained according to the procedure described in Préparation 7 but usingin step 1 the compound obtained in Préparation 3 in which 4-(pyrrolidine-l-sulfonyl)-benzylamine is used in place of 4-fluorobenzylamine in the Step 2. 15 Préparation 10 : tert-butyl 4-(6-iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoate

2.0 g (6.90 mmol) of the compound obtained in Step 1 of Préparation 3 is dissolved in20 approximately 50 ml of DMF, and an excess amount of aqueous ammonium hydroxide isadded. After 10 minutes of stirring, the reaction solution is poured into 100 ml of water,and acidified with concentrated HCl, then extracted with 2x100 ml of EtOAc. Thecombined organic layer is then concentrated to yield 1.8 g (100%) of the desired product as an off-white powder. 012782 41 N.M.R (DMSO-rftf) ’H δ (ppm) : 6.50 (d, 7= 8.8Hz, 1H), 6.68 (s, 2H), 7.12 (s, 1H), 7.33(dd, 7, = 8.8Hz, 72 = 2.1Hz, 1H), 7.77 (d, 7= 1.9Hz, 2H).

1.8 g (6.90 mmol) of compound obtained in the preceding Step 1 is suspended in 30 ml oftriethyI orthoformate. A catalytic amount of para-toluene sulfonic acid is added, and thesuspension is refluxed for 3 hours. Ail volatiles are removed in vacuo, and the residue iswashed with 1:1 dichloromethane:Hexane to yield 1.5 g (80%) of an off white powder as 10 the desired product. MS(APCI), M/z 270.9 (M-l) N.M.R (DMSO-de) 'H δ (ppm) : 7.42 (d, 7= 8.5Hz, 1H), 8.09 (dd, 7, = 8.5Hz, J2 = 2.2Hz,1H), 8.09 (s, 1H), 8.34 (d,7= 2.2Hz, 1H), 12.38 (broad s, 1H). 15 Step 3: tert-Butyl 4-(6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoate

0.9 g (3.31 mmol) of compound obtained in the preceding Step 2 is dissolved in 50 jnl ofDMF. 1.18 g (3.64 mmol) of césium carbonate and 0.986 g (3.64 mmol) of ter-butyl 4-bromomethyl-benzoate is added. The reaction is stirred at room température for 24 hours. 20 200 ml of EtOAc is then added, and then washed with 3 x 100 ml of water. The organic layer is dried over MgSO4 and concentrated. The residue is purified on a silica gel columnusing 4:1 dichloromethane:hexane increasing gradually to a 1;1 ratio, to yield 0.97 g (62%)of white powder as the desired product. MS(APCI), M/z 270.9 (MT ) 25 N.M.R (CDC13) 'H δ (ppm) 5.21 (s, 2H), 7.36 (d, 7= 8.5Hz, 2H), 7.43 (d, 7= 8.5 Hz, 1H),7.96 (dd, 7, = 6.6Hz, 72 = 3.1Hz, 2H), 8.01 (dd, 7, = 6.5Hz, 72 = 2.1Hz, 1H), 8.07 (s, 1H),8.64 (d, 7= 1.8Hz, 1H) 012782 42

Example 1 : 3-(4-Methoxy-benzyI)-4-oxo-3,4-dihydro-quinazoIine-6-carboxyIicacid 4-methoxy-benzylamide

5 0.42 g (1.0 mmol) of the compound of Préparation 1 and 2.1 ml (1.85 g, 12.5 mmol) of triethylorthoformate are stirred for 20 hours at 160°C. After cooling, the precipitateobtained are filtered off, and recrystallized from acetonitrile to yield 0.180 g (yield=42%)of the desired compound. TLC : CH2Cl2/MeOH 90/10 Rf = 0.46 10 N.M.R (DMSO-i/tf) ’H δ (ppm) : 3.75 (2s,6H) ;4.40 (d,2H) ; 5.15 (s,2H) ; 6.85-6.95(m,4H) ; 7.25 (d,2H) ; 7.35 (d,2H) ; 7.75 (d,lH) ; 8.25 (d,lH) ; 8.65 (s,lH) ; 8.70 (s,lH) ;9.25 (t,lH)

IR : 3282, 1661, 1606, 1513, 1248,1032, 841 cm'1MP = 169°C 15 PURITY : HPLC = 96.7%

Example 2 : 3-(4-Metboxy-benzyl)-2-methyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide, hydrochloride

0.42 g (1.0 mmol) of the compound of Préparation 1,1 ml of éthanol at 6% of HCl and 10320 μΐ (100 mg, 1 mmol) of acetylacetone are stirred and then heated ovemight under reflux.

After cooling, the precipitate obtained are filtered off, and recrystallized from acetonitrileto yield the desired compound. TLC : CH2Cl2/MeOH 90/10 Rf = 0.56 N.M.R (DMSO-tfd) 'H δ (ppm) : 2.70 (s,3H) ; 3.75 (s,6H) ;4.45 (d,2H) ; 5.35 (s,2H) ; 6.8525 -6.95 (m,4H); 7.20-7.30 (m,4H) ; 7.30-7.80 (bs,lH) 7.80(d,lH) ; 8.35 (d,lH) ; 8.70 (s,lH) ; 9.35 (t,lH). IR : 3282,1702, 1648, 1634, 1547, 1512,1250, 1178 , 1035, 793 cm'1. 012782 43

MP = 2O8°C PURITY : HPLC = 98.9%

Example 3 : 3-(4-Methox3'-benzyl)-l-methyl-4-oxo-l,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide

To a stirred solution of 0.42 g (1 mmol) of the compound of Préparation 1 in 2 ml ofmethanol are added 75μ1 (1 mmol) of formaldéhyde. The solution obtained is refluxed for1 hour. Then 820 μΐ of a solution of NaOH 2M are added, and the reflux is maintained for20 minutes. After cooling, water is added and the solution extracted wïth ethyl acetate. The 10 organic layer is decanted, dried and concentrated under vacuum. The crude product (0.32 g0.75 mmol) is dissolved into 3 ml of anhydrous DMF and stirred under inert atmosphère.35 mg (0.09 mmol) of NaH are added to this solution and the yellow solution obtained isstirred for 30 minutes at room température and then 55 μΐ (125 mg, 0.9 mmol) of methyliodide are added. After 30 minutes stirring, the reaction mixture is treated as usual and 15 chromatographied over silica gel (dichloromethane/ether) to give the desired compound. N.M.R (DMSO-4) 'H δ (ppm) : 2.85 (s,3H) ; 3.70 (s,6H) ; 4.40 (d,2H) ; 4.50 (s,2H) ; 4.60(s,2H) ; 6.80 -6.95 (m,5H) ; 7.20-7.30 (m,4H) ; 7.95 (d,lH) ; 8.35 (s,lH) ; 8.90 (t,lH) IR: 1637, 1511, 1467, 1247, 1175 cm'1 1

MP=182°C 20 PURITY : HPLC = 95.6%

Example 4 : 3-(4-Methoxy-benzyl)-l,2,2-trimethyI-4-oxo-l,2,3,4-tetrahydro-quinazoline-6-carboxyIic acid 4-methoxy-benzylamide

5 mg of pura-toluenesulfonic acid are added to a stirred solution of 0.42 g of the25 compound of préparation 1 in 3 ml of acetone. The reaction mixture is stirred ovemight at 012782 44 room température. This process is repeated to obtain a complété reaction. The solution isconcentrated under vacuum and the crude product is methylated by addition of methyliôdide in the presence of NaH as described in Example 3. After purification bychromatography, the product obtained is crystallized in a mixture of dichloromethane and 5 ether to give the desired compound. TLC : CH2C12/Aceton 90/10 Rf = 0.36 N.M.R (DMSO-40 Ή δ (ppm) : 1.40 (s,6H) ; 2.90 (s,3H) ; 3.75 (s,6H) ;4.40 (d,2H) ;4.80(s,2H) ; 6.80-6.90 (m,4H) ; 6.95 (d,lH) ; 7.20-7.30 (m,4H) ; 7.90 (d,lH) ; 8.40 (s,lH) ;8.90 (t,lH)

10 IR : 1638, 1608, 1511,1499,1299,1249,1174 cm'1MP=168°C PURITY : HPLC = 96.4%

Example 5 : 4-[6-(4-Methoxy-benzylcarbamoyl)-4-oxo-l,4-dihydro-2JT-quinazolin-

The compound is obtained according to the procedure described in the first step ofExample 3 using as substrate the compound obtained in the Préparation 2TLC : CH2Cl2/MeOH 90/10 Rf = 0.10 - N.M.R (DMSO-<4) ’H δ (ppm) : 3.70 (s,3H) ; 4.35 (d,2H) ;4.60 (s,2H); 4.70 (s,2H) ; 6.75 20 (d,lH) ; 6.85 (d,2H) ; 7.20-7.30 (m,3H) ; 7.45 (d,2H) ; 7.80 (d,lH) ;7.90 (d,2H) ; 8.30(s,lH) ; 8.85 (t,lH) ; 12.85 (bs,lH)

IR : 3314, 1678,1629,1513, 1294,1248 cm'1MP = 270°C PURITY : HPLC = 97.9% 25 012782 45

Example 6 : Methyl 4-[6-(4-Methoxy-benzylcarbamoyl)-l-methyl-4-oxo-l,4-dihydro-2/f-quinazolin-3-ylmethyl]-benzoate

The compound is obtained according to the procedure described in the second step of5 Example 3 using as substrate the compound obtained in the Example 5. TLC : CH2Cl2/MeOH 90 /10 Rf= 0.70 N.M.R (DMSO-^) ‘H δ (ppm) : 2.85 (s,3H) ; 3.70 (s,3H) ;3.85 (s,3H) ; 4.40 (d,2H) ;4.55(s,2H) 4.75 (s,2H) ; 6.80-6.90 (m,3H) ; 7.25 (d,2H) ; 7.45 (d,2H) ; 7.95 (m,3H) ; 8.35(s,lH) ; 8.90 (t,lH)

10 IR : 3370,1720,1651,1631,1608,1514,1475, 1275, 1246,1111 cm'1MP = 175°C PURITY : HPLC = 94.5%

Example 7: 4-[6-(4-Methoxy-benzylcarbanioyl)-l-meihyl-4-oxo-l,4-dihydro-2//-quinazolin-3-ylmethyI]-benzoic acid

The compound is obtained according to the procedure described in the Step 2 ofPréparation 5 using as substrate the compound of Example 6. TLC : CH2Cl2/MeOH 90/10 Rf= 0.35 N.M.R (DMSO-rfd) ’H δ (ppm) : 2.85 (s,3H) ; 3.70 (s,3H) ; 4.40 (d,2H) ; 4.55 (s,2H); 4.7520 (s,2H) ; 6.80-6.90 (m,3H) ; 7.25 (d,2H) ; 7.45 (d,2H) ; 7.95-8.00 (m,3H) ; 8.40 (s,lH) ; 8.90 (t,lH) ; 12.90 (bs,lH) IR : 3540,2740, 1709,1637,1513,1476,1313, 1245,1173 cm’’

MP = 124°C PURITY : HPLC = 95.4% • 25 012782 46

Example 8 : 3-(4-fluorobenzyl)-6-(3-phenyl-pro-l-ynyl)-3 H-quinazoIin-4-one

Το a THF solution of the compound of Préparation 3 (153 mg, 0.40 mmol) andbenzylacetylenylstannane (freshly prepared by addition of «-BuLi to the - 78 °C solution of 5 benzylacetylene, followed by quenching with tributyltin chloride) is added catalyticamount of PdCl2(Ph3P)2 and Cul. The resulting suspension is refluxed for 1 hour andcooled to room température. After filtration and removal of volatiles in vacuo, the residueis purified using flash chromatography to give the desired compound as a white solid (80mg, 54%). 10 N.M.R (CDCh) 'H δ (ppm) 3.87 (s,2H), 5.15 (s,2H), 7.15 (t, J = 8.3 Ηζ,ΙΗ), 7.26-7.43(m,5H), 7.62 (d, J= 8.3 Ηζ,ΙΗ), 7.77 (dd, 7= 8.3, 1.9 Ηζ,ΙΗ), 8.08 (s,lH), 8.39 (d, J= 1.9Ηζ,ΙΗ); MS (APCI), M/z 369.5 (M + 1).

Example 9 : Methyl 4-[4-Oxo-6-(3-phenyI-prop-l-ynyI)-4H-quinazoIin-3-ylmethyl] 15 -benzoate

To a THF solution of the compound of Préparation 4 (165 mg, 0.39 mmol) andbenzylacetylenylstannane (239 mg, 0.59 mmol, freshly prepared by addition of π-BuLi tothe - 78°C solution of benzylacetylene, followed by quenching with tributyltin chloride) is 20 added catalytic amount of Pd(PPh3)2Cl2 and Cul. The resulting suspension is refluxed for 1hour. After filtration and removal of volatiles in vacuo, the residue is purified using flashchromatography to give the desired compound as a white solid. N.M.R (CDC13) ’H δ (ppm) : 3.85 (s,2H), 3.89 (s,3H), 5.23 (s,2H), 7.40 (m,5H), 7.80(s,lH), 8.00 (d, J= 8.3 Hz,2H), 8.40 (s,lH) 25 MS (APCI), M/z 409.5 (M + 1). 012782 47

Example 10 : 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzoicacid

Step 1 : 4-(6-Iodo-4-oxo-4/7-quinazolin-3-ylmethyl)-benzoic acid

5 To a solution of the compound of Préparation 4 (2.25 g, 5.36 rnmol) in 10% H2O in THF isadded LiOH (2.25 g, 53.6 mmol). The reaction is stirred ovemight at room température.After acidification using concentrated HG1, the reaction mixture is extracted with EtOAc.The organic layer is washed with water and brine, dried (MgSO4), filtered andconcentrated in vacuo. The crude product is triturated using a mixture of hexane/EtOAc: 10 4/1 to yield 2.00g of the desired carboxylic acid as a white powder. N.M.R (DMSO-Jd) 'H δ (ppm) : 5.23 (s,2H), 7.40 (d, J = 8.3 Hz,2H), 7.47 (d, J = 8.6Ηζ,ΙΗ), 7.87,(d, J= 8.1,2H), 8.1 (dd, J, = 8.6 Hz, Λ=1.9Ηζ,1Η) 8.38 (d, J= 1.7 Ηζ,ΙΗ),8.59 (s,1H), 12.94 (br s,1H) MS (APCI), M/z 404.9 (Μ * 1). 15 Step 2 : 4-[4-Oxo-6-(3’phenyl-prop-l-ynyl)-4/7-quinazolin-3-ylmethyl]-benzoic acid

To a solution of the compound obtained in Step 1 (0.3 g, 0.739 mmol) in 6.5 ml of DMF, isadded diisopropylethylamine (0.381 g, 2.96 mmol), Cul (catalytic amount), 3-phenyl-l-propyne (0.120 g, 1.03 mmol), and Pd(PPh3)2Cl2 (catalytic amount). The reaction mixture 20 is heated to 50°C for 4 hours. The mixture is then diluted with 150 ml of EtOAc, andwashed with 3x100 ml of water, 1x100 ml of brine. The organic layer is then dried overMgSOzt, and filtered. The filtrate is concentrated in vacuo. The crude product is trituratedwith a mixture of hexane/ethyl acetate: 8/1 to yield 225 mg of the pure desired product as alight yellow solid. 012782 48 N.M.R (DMSO-70) 'H δ (ppm) : 3.91 (s,2H), 5.23 (s,2H), 7.23-7.43 (m,9H), 7.66 (d, 7=8.3Ηζ,ΙΗ), 7.83 (dd, 7,=8.6 Hz, 72=1.7 Ηζ,ΙΗ), 7.87 (br s,lH), 8.09 (d, 7=1.6 Ηζ,ΙΗ), 8.58(s,lH) MS (APCI), M/z 395.1 (Μ + 1). 5 Example 11: 3-(4-fluorobenzyl)-6-(3-phenyI-prop-l-ynyI)-3H-pyrido[3,4-d]pyrimidin-4-one

To a THF solution of a compound of Préparation 5 (0.40 mmol) and benzylacetylenyl stannane (freshly prepared by addition of n-BuLi to the -78°C solution of benzylacetylene,10 followed by quenching with tributyltin chloride) is added a catalytic amount of

PdCl2(Ph3P)2 and Cul. The resulting suspension is refluxed for 1 hour, and cooled toroom température. After filtration and removal of volatiles in vacuo, the residue is purifiedusing flash chromatography on silica gel to give the desired compound.

Example 12: Methyl 4-[6-(3-phenyl-prop-l-ynyI)-4-oxo-4H-pyrido[3,4-d]pyrimidin-15 3-ylmethyl]-benzoate

To a THF solution of the compound of Préparation 6 (0.39 mmol) and benzylacetylenylstannane (239 mg, 0.59 mmol), freshly prepared by addition of n-BuLi tothe -78°C solution of benzylacetylene, followed by quenching with tributyltin chloride) is 20 added catalytic amount of PdCl2(Ph3P)2 and Cul. The resulting suspension is refluxed for1 hour. After filtration and removal of volatile in vacuo, the residue is purified using flashchromatography to give the desired product. 012782 49

Example 13 : 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-4H-pyrido[3,4-d]pyrimidiu-3-yImethyl]-benzoic acid

Step 1: 4-(6-Iodo-4-oxo-4//-pyrido[3,4-i/]pyrimidin-3-ylmethyl)-benzoic acid

To a solution of the compound of Préparation 6 (5.36 mmol), in 10% H2O in THF is added

LiOH (2.25 g, 53.6 mmol). The reaction is stirred ovemight at room température. Afteracidification using concentrated HCl, the reaction mixture is extracted with BtOAc. Theorganic layer is washed with water and brine, dried (MgStXj.) and filtered in vacuo. The crude product is triturated using 4/1 hexane/EtOAc to givp the desired compound. 10

Step 2: 4-[6-(3-phenyl-prop-l-ynyl)-4-oxo-47/-pyrido[3,4-i/]pyrimidin-3-ylmethyl]-benzoic acid

To a solution of the compound obtained in Step 1 (0.739 mmol) in 6.5 ml of DMF, isadded diisopropylethylamine (0.381 g, 2.96 mmol), Cul (catalytic amount), 3-phenyl-1-propyne (0.120 g, 1.03 mmol), and Pd(PPh3)2Cl2 (catalytic amount). The réaction mixture is warmed to 50°C for 4 hours. The mixture is then diluted with 150 ml of EtOAc,and washed with 3x100 ml of water, 1x100 ml of brine. The organic layer is then driedover MgSÛ4 and filtered. The filtrate is concentrated in vacuo. The crude product istriturated with 8/1: hexane/EtOAc to yield the desired compound.

Example 14 : 3-(4-Fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxyIic acid 3-methoxy-benzyIamide

O

MeO. A

O

20 012782 50 0.2 g (0.671 mmol) of the compound obtained in the Préparation 7 is dissolved in 50 ml ofchloroform. 110 mg of 3-methoxybenzyl amine, 205 mg of Mukaiyama reagent and 163mg of triethylamine is added. The reaction solution is then stirred at room températureovemight. The reaction solution is concentrated and purified on silica gel column with 1:1 5 HexanerEtOAc to yield 150 mg of the desired product as an off white solid. N.M.R (CDC13) 'H Ô (ppm) : 3.79 (s, 3H), 4.62 (d, J = 5.6Hz, 2H), 5.13 (s, 2H), 6.63 (s,1H), 6.81-7.34 (m, 8 H), 7.75 (d, J= 8.6Hz, 1H), 8.13 (s, 1H), 8.30 (dd, 7, = 8.6Hz, 72 =2.2Hz, 1H), 8.56 (d, J= 2.0Hz, 1H). 10 Example 15 : 3-(4-MethanesulfonyI-benzyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzyiamide

The compound is obtained according to the procedure described in Example 14 using assubstrate the compound obtained in Préparation 8 and 4-methoxybenzylamine. 15 MS(APCI), M/z 478.1 (M+l) N.M.R (DMSO-Jd) 'H δ (ppm) : 3.18 (s, 3H), 3.72 (s, 3H), 4.39 (d, J= 5.1Hz, 2H), 5.18 (s,2H), 6.87 (d, J= 8.3Hz, 2H), 7.23 (d, J= 8.1Hz, 2H), 7.25 (s, 1H), 7.56 (d, 7= 8.3Hz, 2H),7.85 (d, J= 8.1Hz, 2H), 8.16 (d,7= 8.7Hz, 1H), 8.51 (s, 1H), 9.15 (s, TH). 20

Example 16: 4-Oxo-3-[4-(pyrroIidine-l-suIfonyI)-benzyl]-3,4-dihydro-quinazoIme-6-carboxylic acid 4-methoxy-benzylamide

MeO

H

The compound is obtained according to the procedure described in Example 14 using assubstrate the compound obtained in Préparation 9 and 4-methoxybenzylamine. MS(APCI), M/z 533.2 (M+l)

N.M.R (DMSO-7d) ’H δ (ppm) : 1.59 (s, 4H), 3.07 (s, 4H), 3.68 (s, 3H), 4.39 (d, 7=5.5Hz,2H), 5.29 (s, 2H), 6.85 (d, 7= 8.3Hz, 2H), 7.23 (d, 7= 8.0Hz, 2H), 7.25 (s, 1H), 7.54 (d, J 25 012782 51 = 8.1Hz, 2H), 7.74 (d, J= 8.1Hz, 2H), 8.26 (d, 7= 8.3Hz, 1H), 8.64 (s, 1H), 8.66 (s, 1H),9.27 (s, 1H).

Example 17 : 4-[6-(3-Methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl)-benzoic acid.

The desired product is obtained by foliowing the procedure of Example 14, except 4-flurobenzylamine in step 2 of the préparation 3 is replaced by Zert-butyl 3-aminomethyl-benzoate, and at the end stirring the collected residue in an excess amount of trifluoroaceticacid for 30 minutes at room température. After removing the volatiles in vacuum, theresidue is filtered to fumish the desired product as an off white solid. N.M.R (DMSO-4) ’H Ô (ppm) : 3.71 (s, 3H), 4.43 (d, 7= 4.6Hz, 2H), 5.15 (s, 2H), 6.79(d, J= 7.6H&amp; 1H), 6.86 (s, 2H), 7.20-7.26 (m, 2H), 7.40 (d, J= 7.3Hz, 2H), 7.86 (d, 7 =7.6Hz, 2H), 8.16 (d,7= 8.1Hz, 1H), 8.53 (s, 1H), 9.20 (s, 1H), 11.80 (s, 1H).

Example 18 : 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoIine-3-ylmethyl]-benzoic acid

Step 1: rerZ-Butyl 4-[4-oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazoline-3-ylmethyl]-benzoate

3.0 g (6.48 mmol) of the compound of Préparation 10 is dissolved in 50 ml of DMF. 3.34g (25.9 mmol) of diisopropylethylamine, catalytic amount of copper(I) iodide, 3.01 g (25.9mmol) 3-phenyl-l-propyne and catalytic amount of Pd(PPh3)2Cl2 is then added in thatorder. The reaction solution is stirred at 50°C for 24 hours, then diluted with 300 ml ofEtOAc and washed with 3x200 ml of water, 1x200 ml of brine. The organic layer is driedover MgSCh and concentrated. The residue is purified on silica gel column with 4:1 012782 52

Hexane:EtOAc gradually increasing to 1:1 Hexane:EtOAC to yield a waxy substance asthe desired product. N.M.R (DMSO-J6) ’H δ (ppm) : 1.50 (s, 9H), 5.24 (s, 2H), 7.42 (d, J= 8.8Hz, 2H), 7.49(d, J= 8.6Hz, 1H), 7.84 (d, J= 8.6 Hz, 2H), 8.11 (dd, J, =. 8.6 Hz, J2 = 2.2 Hz, 1H), 8.39 5 (d, 2.0 Hz, 1H), 8.59 (s, 1H).

Step 2: 4-[4-oxo-6-(3-phenyl-prop-1 -ynyl)-4H-quinazoline-3-ylmethyl]-benzoic acid

An excess amount (20 ml) of trifluroacetic acid is added to the compound obtained in the10 preceding Step 1. After 30 minutes of stirring, ail volatiles are removed and the residuetriturated with 1:1 Hexane:EtOAc. The precipitate is collected via filtration and washedwith a small amount of methanol to yield 1.82 g of the desired product as an off-white solid. N.M.R (DMSO-Jd) 'H δ (ppm) : 3.91 (s, 2H), 5.23 (s, 2H), 7.23-7.43 (m, 9H), 7.66 (d, J =15 8.3Hz, 1H), 7.83 (dd, J, = 8.6Hz, J2 = 1.7Hz, 1H), 7.87 (broad s, 1H), 8.09 (d, J= 1.6Hz, 1H), 8.58 (s, 1H).

Example 19 : 4-{6-[3-(4-Methoxy-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazoline-3-

The product is obtained by following the procedure of Example 18, the only différence isthat 3-phenyl-l-propyne used in Step 1 is replaced by l-methoxy-4-prop-2-ynyl-benzene.The product is obtained as a white solid. N.M.R (DMSO-rftf) ’H δ (ppm) : 3.70 (s, 3H), 3.83 (s, 2H), 5.24 (s, 2H), 6.89 (d, J= 8.5Hz,25 2H), 7.29 (d, J= 8.3Hz, 2H), 7.41(d, J= 8.0Hz, 2H), 7.65 (d, J= 8.3Hz, 1H), 7.81 (dd, J, = 8.3Hz, J2 = L5Hz, 1H), 7.88 (d, J= 8.1Hz, 2H), 8.08 (d, J= 1.5Hz, 1H), 8.58 (s, 1H),12.94 (broad s, 1H). 012782 53

Example 20: 4-[4-oxo-6-(3-phenyl-prop-l-ynyI)-4H-quinazoIine-3-ylmethyl]-benzamide

5 0.1 g (0.254 mmol) of the compound of Example 18 is suspended in 50 ml of dichloromethane. 35.4 mg of oxalyl chloride (0.279 mmol) is added, followed by 1 drop ofDMF. The reaction is refluxed under nitrogen for 2 hours, and stirred at room températurefor an additional 12 hours. Then an excess amount of 0.5 M ammonia in dioxane is added.The reaction is stirred at room température for 1 hour. The solvent is then removed in 10 vacuum and the residue is washed-with 1:1 water:methanol to yield 70 mg of an off-whitepowder as the desired product. MS(APCI), M/z 394.1 (M+l). N.M.R (DMSO-Jfi) ’H δ (ppm) : 3.92 (s, 2H), 5.21 (s, 2H), 7.24-7.39 (m, 9H), 7.66 (d, J =8.5 Hz, 1H),-7.80-7.92 (m, 4H), 8.10 (s, 2H), 8.58 (s, 1H). 15

Example 21 : 3-(4-Fluoro-benzyI)-4-oxo-3,4-dihydro-quinazoIine-6-carboxyIic acid(2-methoxy-pyridin-4-ylmethyl)-amide

Compound of the Préparation 7 (227 mg, 0.76 mmol), 2-methoxy-pyridin-4-yl-20 methylamine (138 mg, 1.0 mmol) and the Mukaiyama reagent (256 mg, 1.0 mmol) aredissolved in CHCI3 (10 ml), Et3N (1 ml, excess) is added. The resulting solution is refluxedfor 3 h, cooled to room température. The solution is then purified via a flash chromatography to give the desired product as a white solid, 34 mg, 63% yield. MS (APCI), M/z 419.2 (M+1). 25 N.M.R (DMSO-<4) Ή δ (ppm) : 9.40 (t, J= 5.9 Hz, 1H), 8.70 (s, 1H), 8.69 (s, 1H), 8.28(dd, 1H), 8.07 (d, 7= 5.4 Hz, 1H), 7.77 (d, J= 8.3 Hz, 1H), 7.44 (m, 1H), 7.19 (t, J= 8.7 012782 54

Hz, 1H), 6.91 (d, J= 5.1 Hz, 1H), 6.69 (s, 1H), 5.19 (s, 2H), 4.45 (d, /= 5.9 Hz, 1H), 3.80(s, 3H)

Example 22 : 3-[(3,5-difluoro-4-hydroxy)-benzyl]-6-(3-phenyl-prop-l-ynyI)-3H-quinazoiin-4-one

To a solution of 3-[(3,5-difluoro-4-hydroxy)-benzyl]-6-iodo-3H-quinazolin-4-one(obtained following the procedure of préparation 3 but using in step 2 (3,5-difluoro-4-hydroxy)-benzylamine) (0.3 g, 720 mmol) in 6.5 ml of DMF, is added diisopropylethylamine (0.381 g, 2.96 mmol), 3-phenyl-l-propyne (0.34 g, 2.9 mmol), Cul (catalyticamount), and Pd(PPh3)2Cl2 (catalytic amount). The reaction mixture is heated to 50°C for 4 hours. The mixture is then diluted with 150 ml of EtOAc, and washed with 3x100 ml of s water, 1x100 ml of brine. The organic layer is then dried over MgSC>4 and filtered. Thefiltrate is concentrated in vacuo. The crude product is purified via a flash chromatographyto yield 225 mg of the pure desired product as a light yellow solid. MS (APCI), M/z 403.1 (M + 1). N.M.R (DMSO-4s) 'H δ (ppm) : 8.46 (s, 1H), 8.25 (d, /=2.0 Hz, 1H), 7.1-7.8 (m, 9H),5.20 (s, 2H), 3.91 (s, 2H)

Example 23 : 3-(3-Fluoro-benzyl)-4-oxor3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide

Step 1: 6-Chloro-3-(3-fluoro-benzyl)-3H-pyrido[3,4-d]pyrimidin-4-one

The starting material, 6-chloro-3H-pyrido[3,4-d]pyrimidin-4one (710 mg, 3.92 mmol,prepared according to J. Chem. Soc., Perkin Trans. 1996, 1, 2221) is dissolved in DMF (20ml). Cs2CC>3 (1.66 g, 5.1 mmol) and 3-flurobenzylchloride (737 mg, 5.1 mmol) are added 012782 55 subsequently. The reaction is stirred at room température ovemight, poured into water.After extraction with CH2CI2, the organic layer is washed with H2O and brine, dried(Na2SO4) and filtered. After removal of the solvents, the residue is purified via a flashchromatography to give the product as a white solid. 5 MS (APCI), M/z 290.0 (M + 1). N.M.R (CDCh) ’H Ô (ppm) 8.92 (s, 1H), 8.10 (d, J= 9.6 Hz,2H), 7.0-7.4 (m, 5H), 5.17 (m,2H).

Step 2: Methylcarboxylate 3-(3-fIuorobenzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-

15 20

The compound obtained in the preceding Step 1 (3.0 g, 1.07 mmol), is dissolved in 50 mlof methanol, with an excess amount of triethylamine, and a catalytic amount ofPd(dppf)Cl2. The reaction solution is poured into an autoclave and heated at 100°C for 4hours under the carbon monoxide atmosphère. The reaction is cooled to room températureand filtered. The filtrate is concentrated in vacuum and the residue is purified on a silicagel column using 1:1 Hex:EtOAc to yield the desired product as a white solid (100%). MS (APCI), M/z 314.0 (M + 1). N.M.R (CDC13) lH δ (ppm) : 9.24 (s, 1H), 8.95 (s, 1H), 8.28 (s, 1H), 7.0-7.4 (m, 4H), 5.24(s, 2H), 4.08 (s, 3H)

Step 3: 3-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid3-methoxy-benzylamide

25 To a 0°C solution of 3-methoxybenzylamine (144 mg, 1.05 mmol) in CH2CI2 is addedAlMe3 (0.52 ml, 1.05 mmol). The reaction is stirred at room température for 2 h. Then asolution of the compound obtained in the preceding Step 2 (111 mg, 0.35 mmol) in CH2CI2is added and the resulting reaction is stirred at room température for 2 h, and poured into 012782 56 water. After extraction with CH2CI2, the organic layer is washed with H2O and brine, dried(Na2SC>4) and filtered. After removal of the solvents, the residue is purified via a flashchromatography to give the product as a white solid. MS (APCI), M/z 419.1 (M+l). 5 N.M.R (CDCb) ’H δ (ppm) : 9.40 (t, 1H), 9.09 (s, 1H), 8.76 (s, 1H), 8.54 (s, 1H), 6.7-7.4(m, 11H), 5.22 (s, 2H), 4.45 (d, J= 6.6 Hz, 1H), 3.67 (s, 3H)

Example 24 : 3-(3-FIuoro-benzyI)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide

The compound is obtained according to the procedure of Example 23 using in the Step 3,4-methoxybenzylamine. MS (APCI), l^I/z 419.1 (M + 1). N.M.R (CDC1) ’H δ (ppm) : 9.40 (t, 1H), 9.09 (s, 1H), 8.76 (s, 1H), 8.54 (s, 1H), 7.0-7.415 (m, 9H), 6.80 (d, J= 1.6 Hz, 2H), 5.22 (s, 2H), 4.45 (d, J= 6.6 Hz, 1H), 3.67 (s, 3H)

Example 25 : 4-[4-Oxo-6-(3-phenyl-propa-l,2-dîenyl)-4H-quinazolin-3-ylmethyl]-benzoic acid

20 0.105 g (0.257 mmol) of the compound of Example 9 is dissolved in 25 ml of 90% THF: 10% water. 10 équivalents of LiOH are added. The reaction is refluxed for 3 hours,200 ml of EtOAc are added, acidified by concentrated HCl and the solution is washed with2x100 ml of water and 1x100 ml of brine. Organic layer dried over MgSO4, andconcentrated. The residue is purified on a silica gel column with 95% EtOAc:5% MeOH to 25 yield 30 mg of the product as a light yellow powder. MS(APCI), M/z 481.2 (M+l) 012782 57 N.M.R (DMSO-tf6) Ή δ (ppm) : 5.23 (s, 2H). 6.90 (d, 7= 6.6Hz, 1H), 7.02(d, J = 6.6Hz,1H), 7.24 (m, 1H), 7.33 (d, 7= 4.1,4H), 7.40 (d, 7 = 8.3Hz, 2H), 7.65(d, 7= 8.3Hz, 1H),7.75 (dd, 7, = 8.5Hz, 72= 1.7Hz, 1H), 7.87 (d, 7= 8.1Hz, 2H), 8.07 (s, 1H), 8.53(s, 1H).

Examples 26 to 71 :

These compounds are obtained according to the procedure described in the Préparation 5and Example 8 using the corresponding substrates and reagents. 26. 4-{6-[3-(4-Methoxy-phenyl)-prop-l-ynyl]-4-oxo-477-quinazolin-3-ylmethyl}-benzoic acid, 27. 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l-ynyl]-377-quinazolin-4-one, 28. 4-{6-[3-(3-Methoxy-phenyl)-prop-l-ynyl]-4-oxo-4//-quinazolin-3-ylmethyl}-benzoic acid, 29. 3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methoxy-phenyl)-prop-l-ynyl]-3/7-quinazolin-4-one, 30. 4-[4-oxo-6-(3-pyridin-4-yl-prop-l-ynyl)-477-quinazolin-3-ylmethyl]-benzoicacid, 31. 3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-4-yl-prop-l-ynyl)-377-quinazolin-4-one 32. 4-[4-oxo-6-(3-pyridin-3-yl-prop-l-ynyl)-4//-quinazolin-3-ylmethyl]-benzoic. acid, 33. 3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-3-yl-prop-l-ynyl)-377-quinazolin-4-one, 34. 4- {6-[3-(4-fluro-phenyl)-prop-l-ynyl]-4-oxo-4/i-quinazolin-3-ylmethyl} -benzoicacid, 3 5. 6-[3-(4-Fluro-phenyl)-prop-1 -ynyl]-3-(4-methanesulfonyl-benzyl)-377-quinazoIin-4-one, 36. 4- {6-[3-(3-fluro-phenyl)-prop-l-ynyl]-4-oxo-477'-quinazolin-3-ylmethyl} -benzoicacid, 37. 6-[3-(3-Fluro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3/7-quinazolin-4-one, 012782 58 38. 4-{6-[3-(4-chloro-phenyl)-prop-l-ynyl]-4-oxo-477-quinazolin-3-ylmethyl}-benzoic acid, 39. 6-[3-(4-Chloro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-377-quinazolin-4-one, 40. 4-{6-[3-(3-chloro-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl}-benzoic acid, 41. 6-[3-(3-Chloro-phenyl)-prop-1 -ynyl]-3-(4-methanesulfonyl-benzyl)-377-quinazolin-4-one, 42. 4- {6-[3-(4-bromo-phenyl)-prop-1 -ynyl]-4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid, 43. 6-[3-(4-bromo-phenyl)-prop-1-yn yl]-3-(4-meth anesulfonyl-benzy 1)-377-quinazolin-4-one, 44. 4- {6-[3-(3-bromo-phenyl)-prop-1 -ynyl]-4-oxo-47/-quinazolin-3-ylmethyl} -benzoic acid, 45. 6-[3-(3-bromo-phenyl)-prop-1 -ynyl]-3-(4-methanesulfonyl-benzyl)-3/7- $ quinazolin-4-one, 46. 4-{6-[3-(4-nitro-phenyl)-prop-l-ynyl]-4-oxo-4H-quinazolin-3-ylmethyl} -benzoicacid, 47. 3-(4-Methanesulfonyl-benzyI)-6-[3-(4-nitro-phenyl)-prop-l-ynyl]-377-quinazolin-4-one, 48. 4- {6-[3-(2-methoxy-pyridin-4-yl)-prop-l-ynyl]-4-oxo-477-quinazolin-3-ylmethyl}-benzoic acid, 49. 3-(4-Methanesulfonyl-benzyl)-6-[3-(2-methoxy-pyridin-4-yl)-prop-l-ynyl]-377-quinazolin-4-one, 50. 4-{6-[3-(4-methylsulfanyl-phenyl)-prop-l-ynyl]-4-oxo-477-quinazolin-3-ylmethyl}-benzoic acid. 51. 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-methylsulfanyl-phenyl)-prop-1 -ynyl]-377-quinazolin-4-one 52. 4-{6-[3-(3-methyIsulfanyl-phenyl)-prop-l-ynyl]-4-oxo-477-quinazolin-3-ylmethyl}-benzoic acid 53. 3-(4-MethanesulfonyI-benzyl)-6-[3-(3-methylsulfanyl-phenyl)-prop-l-ynyl]-3/7-quinazolin-4-one 012782 59 15 20 25 54. 4-[4-oxo-6-(3-p-tolyl-prop-1 -ynyl)-4H-quinazolin<3-ylrnethyl]-benzoic acid 55. 3-(4-Methanesulfonyl-benzyl)-6-(3-/?-tolyl-prop-l-ynyl)-377-quinazolin-4-one 56. 4-[4-oxo-6-(3-m-tolyl-prop-l -ynyl)-427-quinazolin-3-ylmethyl]-benzoic acid 57. 3 -(4-Methanesulfonyl-benzyl)-6-(3 -zn-tolyl-prop-1 -ynyl)-3//-quinazolin-4-one 58. 4-[6-(3-Imidazol-l-yl-prop-l-ynyî)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoicacid 59. 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzenesulfonamide 60. 4-[4-Oxo-6-(3-phenyl-prop-l-ynyl)-4H-quinazolin-3-ylmethyl]-benzonitrile 61. 3-(3-Chloro-benzyl)-6-(4-phenyl-but-1 -ynyl)-3H-quinazolin-4-one 62. 3-(3-Chloro-benzyl)-6-(3-phenyl-prop-l-ynyl)-3H-quinazolin-4-one 63. 4-[4-Oxo-6-(3-pyrazol-1 -yl-prop-1 -ynyl)-4H-quinazolin-3-ylmethyl]-benzoicacid 64. 6-(3-Phenyl-prop-1 -ynyl)-3-[4-(lH-tetrazol-5-yl)-benzyl]-3H-quinazolin-4-one 65. 3 -(3 ^4-Difluoro-benzyl)-6-[3 -(pyri din-4-yloxy)-prop-1 -ynyl]-3H-quinazo lin-4-one 66. 3-(3,4-Difluoro-benzyl)-6-[3-(4-methoxy-phenyl)-prop-l-ynylJ-3H-quinazoIin-4-one 67. N- {4-[4-Oxo-6-(3-phenyl-prop-1 -ynyl)-4H-quinazolin-3-ylmethyl]-phenyl} -acetamide 68. 3-(3,4-Difluoro-benzyl)-6-(3-phenyl-prop-l-ynyl)-3H-quinazolin-4-one 69. _3-(4-Acetyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-1 -ynyl]-3H-quinazolin-4-one 70. 6-(3-Phenyl-prop-1 -ynyl)-3-pyridin-4-ylmethyl-3H-quinazolin-4-one 71. 6-[3-(4-Methoxy-phenyl)-prop-1 -ynyl]-3-pyridin-4-ylinethyl-3H-qumazolin-4-one

Examples 72 to 103 :

These compounds are obtained according to the procedure described in the Préparation 6and Example 11 using the corresponding substrates and reagents. 30 72. 4- {6-[3-(4-methoxy-phenyl)-prop-l -ynyl]-4-oxo-4H-pyrido[3,4-J]pyrimidin-3- ylmethyl}-benzoic acid, 012782 60 73. 3-(4-methanesulfonyl-benzyl)-6-[3-(4-methoxyl-phenyl)-prop-l-ynyl]-3H-pyrido[3,4-<7]pyrimidin-4-one, 74. 4-{6-[3-(3-methoxy-phenyl)-prop-l-ynyl]-4-oxo-477-pyrido[3,4-i/]pyrimidin-3-ylmethyl}-benzoic acid, 7 5. 3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methoxyl-phenyl)-prop-1 -ynyl]-377-pyrido[3,4-i/]pyrimidin-4-one, 76. 4-[4-oxo-6-(3-pyridin-4-yl-prop-l-ynyl)-47/-pyrido[3,4-i7]pyrimidin-3-ylmethyl]-benzoic acid, 77. 3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-4-yl-prop-l-ynyl)-377-pyrido[3,4-ûQpyrimidin-4-one, 78. 4-[4-oxo-6-(3-pyridin-3-yl-prop-l-ynyI)-477-pyrido[3,4-i/]pyriniidin-3-ylmethyl]-benzoic acid, 79. 3-(4-Methanesulfonyl-benzyl)-6-(3-pyridin-3-yl-prop-l-ynyl)-377-pyrido[3,4-<7]pyrimidm-4-one, 80. 4- {6- [3 -(4-fluro-phenyl)-prop-1 -ynyl] -4-oxo-477-pyrido [3,4-i/]pyrimidin-3 -ylmethyl} -benzoic acid, 81. 6-[3-(4-Fluro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3H-pyrido[3,4-i/]pyrimidin-4-one, 82. 4-{6-[3-(3-fluro-phenyl)-prop-l-ynyl]-4-oxo-4Z/-pyrido[3,4-ii]pyrimidin-3-ylmethyl}-benzoic acid, 83. 6-[3-(3-Fluro-phenyl)-prop-1 -ynyl]-3-(4-methanesulfonyl-benzyl)-377-. pyrido[3,4-ûTJpyrimidin-4-one, 84. 4- {6-[3-(4-chIoro-phenyl)-prop-l -ynyl]-4-oxo-4#-pyrido[3,4-d]pyrirnidin-3-ylmethyl}-benzoic acid, 85. 6-[3-(4-Chloro-phenyl)-prop-1 -ynyl]-3-(4-methanesulfonyl-benzyl)-377-pyrido[3,4-d]pyrimidin-4-one, 86. 4-{6-[3-(3-chloro-phenyl)-prop-l-ynyl]-4-oxo-477-pyrido[3,4-iflpyrimidin-3-ylmethyl}-benzoic acid, 87. 6-[3-(3-Chloro-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-377-pyrido[3,4-i/]pyrimidin-4-one, 88. 4-{6-[3-(4-bromo-phenyl)-prop-l-ynyl]-4-oxo-477-pyrido[3,4-ifIpyrimidin-3-ylmethyl) -benzoic acid, 012782 10 15 20 25 61 89. 6-[3-(4-Bromo-phenyl)-prop-l-ynyl]-3-(4-methanesulfonyl-benzyl)-3//-pyrido[3,4-6Qpyrimidin-4-one, 90. 4-{6-[3-(3-bromo-phenyl)-prop-l-ynyl]-4-oxo-4Jï-pyrido[3;4-</]pyrimidin-3-ylmethyl}-benzoic acid, 91. 6-[3-(3-Bromo-phenyI)-prop4 -ynyl]-3-(4-methanesulfonyl-benzyl)-3H-pyrido[3,4-^pyrimidin-4-one, 92. 4- {6-[3-(4-nitro-phen.yl)-prop-l -ynyl]-4-oxo-4//'-pyrido[3,4-fiQpyrimidin-3-ylmethyl}-benzoic acid, 93.. 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-nitro-phenyl)-prop-1 -ynyl)-3#-pyrido[3,4</jpyrimidin-4-one, 94. 4- {6-[3-(2-methoxy-pyridin-4yl)-prop-1 -ynyl]-4-oxo-477-pyrido[3,4-d]pyrimidin3-ylmeîhyl}-benzoic acid, 95. 3-(4-Methanesulfonyl-benzyl)-6-[3-(2-methoxy-pyridin-4-yl)-prop-l-ynyl)-3i7-pyrido[3,4-d]pyrimidin-4-one, 96. 4-{6-[3-(4-methylsulfanyl-phenyl)-prop-l-ynyl]-4-oxo-4jyr-pyrido[3,4-ifjpyrimidin-3-ylmethyl}-benzoic acid, 97. 3-(4-Methanesulfonyl-benzyl)-6-[3-(4-methylsulfanyl-phenyl)-prop-1 -ynyl)-377-pyrido[3,4-d]pyrimidin-4-one, 98. 4- {6-[3-(3-metliylsulfanyl-phenyl)-prop-l -ynyl]-4-oxo-477-pyrido[3,4-ifjpyrimidin-3-ylmethyl} -benzoic acid, 99. 3-(4-Methanesulfonyl-benzyl)-6-[3-(3-methylsulfanyl-phenyl)-prop-1 -ynyl)-3/f- pyrido[3,4-i/]pyrimidin-4-one, - 100. 4-[4-oxo-6-(3-/?-iolyl-prop-1 -ynyl)-47/-pyrido[3,4-i/]pyrimidin-3-ylmethyl]-benzoic acid, 101. 3-(4-Methanesulfonyl-benzyl)-6-(3-p-tolyl-prop-1 -ynyl)-377-pyrido[3,4-ûQpyrimidin-4-one, 102. 4-[4-oxo-6-(3-/72-tolyl-prop-l-ynyl)-47ï-pyrido[3,4-ii}pyriniidin-3-ylmethyl]-benzoic acid, 103. and 3-(4-Methanesulfonyl-benzyî)-6-(3-7?2-tolyl-prop-l-ynyl)-3H-pyrido[3,4·d]pyrimidin-4-one.

Examples 104 and 105 30 012782 62

These compounds are obtained according to the procedure described in Examples 14 and21 using the corresponding substrates and reagents. 104. 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoiine-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide 5 105. 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4- methoxy-benzylamide

PHARMACOLOGIC AL STUPIES OF COMPOUNDS OF THE INVENTION

Example 106 : Evaluation of the in vitro activity of the MMP-13 inhibitor compoundsaccording to the invention. 10 The inhibitory activity of the compounds of formula (I) according to the invention withrespect to matrix metalloprotease-13 is evaluated by testing the ability of the compounds ofthe invention to inhibit the proteolysis of a peptide substrate with MMP-13.

The peptide substrate used in the test is the following peptide: Ac-Pro-Leu-Gly-thioester-Leu-Leu-Glÿ-OEt. 15 The inhibitory activity of a compound of formula (I) according to the invention isexpressed as the IC50 value, which is the concentration of inhibitor for which an inhibitionof 50% of the activity of the matrix metalloprotease under considération is observed.

To carry out this test, a reaction medium of 100 μΐ volume is prepared, containing: 50 mMof HEPES buffer, 10 mM of CaCb and 1 mM of 5,5’-dithiobis-(2-nitrobenzoic'acid) 20 (DTNB), and 100 μΜ of substrate, the pH being adjusted to 7.0.

Increasing concentrations of the inhibitory compound présent in a 2.0% DMSO solutionand 2.5 nM of the catalytic domain of human MMP-13 are added to the test samples.

The concentrations of inhibitors présent in the test samples range from 100 μΜ to 0.5 nM.The measurement of the proteolysis of the substrate peptide is monitored by measuring the 25 absorbence at 405 nm using a spectrophotometer for reading microplates, at the laboratorytempérature, the measurements being carried out continuousîy for 10 to 15 minutes.

The IC50 values are calculated from a curve in which the percentage of the catalyticactivity relative to the control is represented on the X-axis and the concentration ofinhibitor is represented on tire Y-axis. 012782 63

The IC50 values on MMP-13 of the compounds of Examples 1 to 10,14-19, 21,23-25, 58-60, 62, 64-71, 104, 105 are ail below 1 μΜ.

The test described above for the inhibition of MMP-13 was also adapted and used todétermine the ability of the compounds of formula (I) to inhibit the matrix 5 métalloprotéases MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 and MMP-14.

The results obtained show that the compounds according to the invention generally hâveIC50 values for MMP-13 which are about 100 times lower than the IC50 values for the samecompounds with respect to the other matrix métalloprotéases tested. 10

Claims (19)

1. 012782 64 CLAIMS

   wherein : • Xi represents a group -CR3 in which R3 represents a hydrogen atom, • X2 represents a nitrogen atom or a group -CR3 in which R3 represents a hydrogen atom, • X3 represents a group -CR3 in which R3 represents a hydrogen atom, • Gi represents a group selected from those of formulae (i/a) and (i/b):

   (i/a) (i/b) 10 in which: . the carbon atom with number 2 is attached to the group N-Ri in the ring, R4 and R5, identical or different, independently of each other, represent a groupselected from hydrogen and (Ci-Cg)alkyl, - Rô represents a group selected from hydrogen and (Ci-Cô)alkyl, 15 20 • G2 represents a group selected from carbon-carbon triple bond and a group of formula(i/c): - V ™ Y, in which the carbon atom with number 1 is attached to the bicycle of the compound offormula (I), Y| represents oxygen or sulphur and Y2 represents -NH or -N(C|-C6)alkyI, n represents 0 or 1 012782 65 • Zi représente -CR9R10, wherein R9 and Rio, identical or different independently of eachother, represent a group selected from hydrogen and (Ci-Cg)alkyl, • Ri représente the group of formula (i/d) :

   S in which p is 1, S 7a représente -CR11R12 wherein Ru and R12, identical or different independentlyof each other, represent a group selected from hydrogen and (Ci-Cô)alkyl, 7 B représente a phenyl group, 7 q is equal to 0 or 1, and 7 G3S when it is présent, représente a group selected from OR13, halogen, S(O)kiRi3and C(=O)ORi3 in which R13 représente an hydrogen atom or a (Ci-Cg) alkyl group,and ki is two, • A represents a groups selected from phenyl and pyridyl, • m is equal to one, and • R2 represents a (Ci-Cô)alkoxy group or a hydrogen atom, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, '_and thepharmaceutically acceptable salts thereof.
2. 2- A compound according to Claim 1 wherein G, represents a group of formula (i/a) :

   (i/a) '4 wherein R4 représente hydrogen or (C|-Cô) alkyl, 012782 66 optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and thepharmaceutically acceptable salts thereof,
3. 3- A compound according to Claim 1 wherein : • G2 represents a group of formula (i/c): Y (i/c) in which the carbon atom with number 1 is attached to the bicycle of the compound of formula (I), Yi represents -NH and Y2 represents oxygen and, optionally, the racemicforms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable saltsthereof. 10
4. 4- A compound according to Claim 1 wherein : • G2 represents a carbon-carbon triple bond, • n is 1, • Zi is as defined in Claim 1, • A represents a phenyl group, 15 · R| is as defined in Claim 1, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and thepharmaceutically acceptable salts thereof, 20
5. 5- A compound according to Claim 1 wherein Z2 represents a group -CRi 1 Ri2 in which Ri 1 and R12 represents an hydrogen atom, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and thepharmaceutically acceptable salts thereof,
6. 6- A compound according to claim 1 wherein Gi represent a group of formula (i/a) in25 which R4 represents a hydrogen atom or a methyl group, or a group of formula (i/b) inwhich R4 and R5, identical, represent each a hydrogen atom or a methyl group, and Ré represents a hydrogen atom or a methyl group, 012782 67 optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and thepharmaceutically acceptable salts thereof.
7. 7- A compound according to claim 1 wherein G2 represent a carbon-carbon triple bond or agroup of formula (i/c) (i/c) in which Y1 represents an oxygen atom, and Y2 represents a group -NH, optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and thepharmaceutically acceptable salts thereof.
8. 8- A compound according to claim 1 wherein Z| represents -CR9R10 in which R9 and Riorepresent each a hydrogen atom, and n is one, optionally,s the racemic forms thereof, isomers thereof, N-oxides thereof, and thepharmaceutically acceptable salts thereof.
9. 9- A compound according to claim 1, which is selected from : - 3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide - 3-(4-methoxy-benzyl)-2-methyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic -acid 4-mëthoxy-benzylamide, hydrochloride - 3-(4-methoxy-benzyl)-l-methyl-4-oxo-l,2,3,4-tetrahydro-quinazoline-6-carboxylicacid 4-methoxy-benzylamide - 3-(4-methoxy-benzyl)-1,2,2-trimethyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide - 4-[6-(4-methoxy-benzylcarbamoyl)-4-oxo-l,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid - 4-[6-(4-methoxy-benzylcarbamoyl)-l-methyl -4-oxo- l,4-dihydro-2H-quinazolin-3-ylmethylj-benzoic acid methyl ester 012782 68 4-[6-(4-methoxy-benzylcarbamoyl)-l-methyl-4-oxo-l,4-dihydro-2H-quinazolin-3-ylmethylj-benzoic acid, - 3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 3-methoxy- benzylamide - 3-(4-methanesulfonyl-benzyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide - 4-Oxo-3-[4-(pyrrolidine-l-Sulfonyl)-benzyl]-3,4-dihydro-quinazoline-6-carboxylic acid4-methoxy-benzylamide - 4-[6-(3-methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyI]-benzoic acid, - 3.-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy- pyridin-4-ylmethyl)-amide, 3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide, 3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide - 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide and 3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide.
10. 10- A process for the préparation of compounds according to claim 1, comprising reactinga compound of formula (V)

    in which Xi, X2, X3, Yi, Y2, Zi, R2, Ri, A, n and m are as defined in Claim 1 • either with triethyl orthoformate under heating condition, to yield the compound offormula (I/a), which is a particular case of the compound of formula (I): 012782 69

    R, (I/a) in which Xi, X2, X3, Yi, Y2, Zi, R2, Ri, A, n and m are as defined hereinbefore, • or under heating condition in the presence of acid, with a compound of formula (VI): W (VD0 0 in which R4 has the same définition as the compound of formula (I), to yield the compoundof formula (I/b), which is a particular case of the compound of formula (I):

    R, (I/b) in which Xi, X2, X3, Yi, Y2, Zi, R2, Ri, R4, A, n and m are as defined hereinbefore, or with a compound of formula (VII) in basic conditions: (VH) 10 O in which R4 and R5 hâve the same définition as the compound of formula (I), to yield the compound of formula (I/c), which is a particular case of the compound offormula (I):

    (I/c) 15 in which Xh X2, X3, Yi, Y2, Zi, R2, Ri, R4, R5, A, n and m are as defined hereinbefore, 012782 70 which compound of formula (I/c) is optionally treated with a hydride, in the présence of acompound of formula (VIII): Ri-Hal (VIII) in which R$ has the same définition as the compound of formula (I), to yield the compound of formula (I/d), which is a particular case of the compound offormula (I):

    (I/d) in which X|, X2, X3, Yi, Y2, Zj, R2, Ri, R4, R5, Ri, A, n and m are as defined hereinbefore, the compounds of formulae (I/a), (I/b), (I/c) and (I/d) being purified, where appropriate,10 according to a conventional purification technique, separated, where appropriate, into theirdifferent isomers according to a conventional séparation technique, and converted, whereappropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into an N-oxide thereof. 15
11. 11- A process for the préparation of compounds according to Claim 1 comprising reactinga compound of formula (XlII/e)

    (XIH/e) in which Xj, X2, X3, Ri and Gi are as defined for the compound of formula (I), and Hal is ahalogen atom, with a compound of formula (XV) : ^CH (XV) 20 012782 in which Zj, R2, A, n and m hâve the same définitions as the compound of formula (I),in the presence of dichlorobis(triphenylphosphine)palladium, cupper iodide and N,N’~diisopropylethylamine in dimethylformamide, 5 to yield the compound of formula (I/e), which is a particular case of the compound offormula (I):

    in which Xi, X2, X3, Ri, Gi, Zi, R2, A, n and m hâve the same définitions as for thecompound of formula (I). 10
12. 12 - A process for the préparation of compounds according to claim 1, comprising reactinga compound of formula (XlII/e) :

    (XlII/e) in which Xb X2, X3, Ri and Gi are as defined in the compound of formula (I), and Hal is ahalogen atom, 15 with carbon monoxide in an alkaline medium in the presence of a protic solvent and acatalytic amount of palladium, to yield the compound of formula (XVI) :

    (XVI) in which Xt, X2, X3, Ri and Gi are as defined in the compound of formula (I), 20 and further hydrolyzing the compound of formula (XVI) under basic conditions to yieldthe compound of formula (XVII): 72 01278 2*

    (XVII) in which Xb X2, X3, Ri and Gi are as defined in the compound of formula (I), and fiirther condensing the compound of formula (XVII) under basic conditions in the5 presence of a Mukayama reagent, on the compound of formula (XVIII): (xvm) in which Zb R2, A, n and m hâve the same définitions as for the compound of formula (I), to yield the compound of formula (I/f), which is a particular case of the compound of10 formula (I):

    in which X]; X2, X3, Zj, R2, Rj, A, n and m are as defined hereinbefore, whichcompounds of formula (I/f) are purified, where appropriate, according to a conventionalpurification technique, or separated, where appropriate, into their different isomers 15 according to a conventional séparation technique, and converted, where appropriate, intoaddition salts thereof with a pharmaceutically-acceptable acid or base, or into anlN-oxidethereof.
13. 13- A pharmaceutical composition comprising as active ingrédient an effective amount of acompound as claimed in claim 1, alone or in combination with one or more 20 pharmaceutically-acceptable excipients or carriers. 012782 73
14. 14- A pharmaceutical composition useful in the treatment of a living bodyafflicted with a disease where the inhibition of type -13 matrix metalloprotease isinvolved, comprising as active ingrédient an effective amount of a compound asclaimed in any of daims 1 to 9 together with one or more pharmaceutically-acceptable excipients or carriers.
15. 15- The use of a compound according to Claim 1, for the préparation of a médicinal product intended for treating a disease involving therapy by inhibition of type-13 matrixmétalloprotéases.
16. 16- The use according to Claim 14 wherein the disease is arthritis, rheumatoid arthritis,osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, 10 multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructivepulmonary disease, age-related macular degeneration, and cancers.
17. 17- The use according to Claim 16 wherein the disease is arthritis.
18. 18- The use according to Claim 16 wherein the disease is osteoarthritis.
19. 19- The use according to Claim 16 wherein the disease is rheumatoid arthritis. 20