JP2005526070A - Oxo-azabicyclic compounds - Google Patents

Abstract

A compound selected from formula (I): X ₁ , X ₂ , and X ₃ represent N or —CR ₃ , wherein R ₃ is as described in the specification, and G ₁ Represents a group selected from formulas (i / a) and (i / b), wherein R ₄ , R ₅ , and R ₆ are as described in the specification and G ₂ is carbon -Carbon triple bond, -CH = C = CH-, C = O, C = S, S (O) _n1 (n1 represents an integer of 0 to 2) or formula (i / c) (wherein Y ₁ represents O, S, —NH or —N-alkyl, Y ₂ represents a group selected from O, S, —NH or —N-alkyl), and n is 0 to 6 M represents an integer of 0 to 7, Z ₁ represents —CR ₉ R ₁₀ , wherein R ₉ and R ₁₀ are as described in the specification, and A represents a ring system R ₁ is H, alkyl, alkenyl, alkyl Nyl and optionally substituted and selected from the group of formula (i / d) wherein p, Z ₂ , B, q and G ₃ are as described in the specification Compounds, optionally optical isomers thereof, N-oxides, and addition salts with pharmaceutically acceptable acids or bases, and pharmaceuticals containing them are specific for type 13 matrix metalloproteinases Useful as a chemical inhibitor.
[Chemical 1]

Description

Field of Invention

  The present invention relates to novel oxo-aza bicyclic compounds that are useful in the manufacture of a medicament for treating diseases involving therapy with matrix metalloproteinase-13 (MMP-13) inhibitors. These medicaments are particularly useful for the treatment of certain inflammatory conditions such as rheumatoid arthritis or osteoarthritis, as well as certain proliferative conditions such as cancer.

Technical background of the invention

  Matrix metalloproteinase (MMP) is an enzyme involved in the renewal of extracellular matrix tissues such as cartilage, tendons and joints. MMP causes destruction of extracellular matrix tissue, but in non-pathological physiological conditions it is compensated by its simultaneous regeneration.

  Under normal physiological conditions, these highly active peptidase activities are controlled by specialized proteins that inhibit MMPs, such as the metalloprotease tissue inhibitor (TIMP).

  Local balance of MMP and TIMP activity is important for the renewal of the extracellular matrix. This change in equilibrium leading to excess active MMP in connection with inhibitors of MMP induces the pathological destruction of cartilage observed especially in rheumatoid arthritis and osteoarthritis.

  In pathological situations, irreversible deterioration of the articular cartilage occurs, as in the case of rheumatic diseases such as rheumatoid arthritis or osteoarthritis. In these conditions, the cartilage degradation process prevails, causing tissue destruction and loss of function.

  At least 20 different matrix metalloproteases have been identified so far, each subdivided into 4 groups: collagenase, gelatinase, stromelysin and membrane-type MMP (MT-MMP).

  Matrix metalloproteinase-13 (MMP-13) is a collagenase-type MMP that constitutes the dominant collagenase observed during osteoarthritis in which chondrocytes drive cartilage destruction during their pathology.

  Arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, inflammatory bowel disease, psoriasis, multiple sclerosis, heart failure, atherosclerosis, asthma, chronic obstructive pulmonary disease (COPD), age-related macular In order to prevent and / or correct imbalances in the renewal of extracellular matrix tissues such as degeneration (ARMD) and cancer, there is a need for new MMP inhibitors, more specifically MMP-13 inhibitors. Exists.

  MMP inhibitory compounds are known. Most of these MMP inhibitors are not selective for a single MMP, such as those described by Montana and Baxter (2000) or Clark et al. (2000).

  There is also a need in the prior art for new inhibitors that are active on matrix metalloproteinase-13 in order to enrich the therapeutic tools that can be used to treat extracellular matrix destruction and cancer-associated conditions. It has been.

WO 98/26664 describes quinazolinone compounds used as novel antifungal compounds.
The compounds of the present invention are novel and represent a potent inhibitor of MMP-13. Therefore, they are rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, inflammatory bowel disease, psoriasis, multiple sclerosis, heart failure, atherosclerosis, asthma, chronic obstructive pulmonary disease (COPD), There are applications in the treatment of age-related macular degeneration (ARMD) and cancer.

Summary of the Invention

The Applicant has identified novel oxoazabicyclic compounds that are matrix metalloproteinase inhibitors, and more particularly compounds that are selective MMP-13 inhibitors.
More particularly, the present invention is a compound of the formula (I):

{In the formula:
X ₁ , X ₂ , and X ₃ each independently represent a nitrogen atom or a group —CR ₃ , where R ₃ is hydrogen, (C ₁ -C ₆ ) alkyl, amino, mono (C ₁ -C ₆₎ represents alkylamino, di (C ₁ ~C ₆₎ alkylamino, hydroxy, a group selected (C ₁ ~C ₆₎ alkoxy, and halogen, with the proviso that the groups X _1, X _2, and X 2 or less of ₃ simultaneously represents a nitrogen atom;
G ₁ is the formula (i / a) and (i / b):

[Where:
The carbon atom having the number 2 is bonded to the group N—R ₁ in the ring;
R ₄ and R ₅ may be the same or different and are independently of each other hydrogen, (C ₁ -C ₆ ) alkyl, aryl, aryl (C ₁ -C ₆ ) alkyl, cycloalkyl, cycloalkyl (C _1- C ₆ ) represents a group selected from alkyl, heteroaryl, heteroaryl (C ₁ -C ₆ ) alkyl, heterocycloalkyl, and heterocycloalkyl (C ₁ -C ₆ ) alkyl;
R ₆ is
Hydrogen, trifluoromethyl, OR ₇ , NR ₇ R ₈ (R ₇ and R ₈ may be the same or different and each independently represents hydrogen or (C ₁ -C ₆ ) alkyl),
(C ₁ ~C ₆₎ alkyl, (C ₂ ~C ₆₎ alkenyl, (C ₂ ~C ₆₎ alkynyl, aryl, aryl (C ₁ ~C ₆₎ alkyl, cycloalkyl (C ₁ ~C ₆₎ alkyl, Heteroaryl, heteroaryl (C ₁ -C ₆ ) alkyl, heterocycloalkyl, and heterocycloalkyl (C ₁ -C ₆ ) alkyl, including halogen, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino (each alkyl moiety may be the same or different and are independent of each other), cyano, trihalogeno (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acyl,- One or more selected from C (═O) OR ₇ , —OR ₇ and —SR ₇ (where R ₇ is as defined above), which may be the same or different, and are substituted by groups independent of each other. Even if It represents a group selected from the casting. ]
A group selected from:
G ₂ is a carbon-carbon triple bond, —CH═C═CH—, C═O, C═S, S (O) _n1 (n1 represents an integer of 0 to 2), and a formula (i / c ):

[Where:
The carbon atom having the number 1 is attached to the bicyclic ring of the compound of formula (I) and Y ₁ is selected from oxygen, sulfur, —NH and —N (C ₁ -C ₆ ) alkyl. And Y ₂ represents a group selected from oxygen, sulfur, —NH and —N (C ₁ -C ₆ ) alkyl. ]
Represents a group selected from:
-N represents an integer of 0-6;
Z ₁ represents —CR ₉ R ₁₀ , and R ₉ and R ₁₀ may be the same or different, and independently of each other, hydrogen, (C ₁ -C ₆ ) alkyl, trihalogeno (C ₁ -C ₆ ) Alkyl, halogen, —OR ₇ , —SR ₇ , —C (═O) OR ₇ (R ₇ is as defined above), amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆₎ alkylamino (the alkyl moiety thereof represents a group selected from a well independently be the same or different), and when n is equal to greater than or 2, the hydrocarbon chain Z ₁ is Can contain 1 to 2 isolated or conjugated multiple bonds, and / or
When n is greater than or equal to 2, one of the —CR ₉ R ₁₀ is oxygen, S (O) _n1 (where n1 is as defined above), —NH and —N (C _1- C ₆ ) may be substituted with a group selected from alkyl;
A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, and these rings are 5-membered or 6-membered monocycles or are composed of two 5-membered or 6-membered monocycles A bicyclic ring;
・ R ₁ is
hydrogen,
(C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, amino, cyano, trihalogeno (C ₁ -C ₆ ) alkyl, cycloalkyl, —C ( ═O) NR ₇ R ₈ , —C (═O) OR ₈ , —OR ₈ , —SR ₈ (R ₇ and R ₈ may be the same or different and independently of each other hydrogen or (C ₁ -C ₆ ) representing alkyl) one or more selected from the same or different, optionally substituted with groups independent of each other, and
Formula (i / d):

[Where:
p is an integer of 0 to 8,
Z ₂ represents —CR ₁₁ R ₁₂ , and R ₁₁ and R ₁₂ may be the same or different, and independently of each other, hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, trihalogeno (C ₁ -C ₆ ) Represents a group selected from alkyl, halogen, amino, —OR ₇ , —SR ₇ and —C (═O) OR _{7, where} R ₇ represents hydrogen or (C ₁ -C ₆ ) alkyl, and p Is greater than or equal to ₂ , the hydrocarbon chain Z ₂ can contain 1 or 2 isolated or conjugated multiple bonds, and / or
When n is greater than or equal to 2, one of the —CR ₁₁ R ₁₂ is oxygen, S (O) _n1 (n1 is as defined above), —NH, —N (C _1- C ₆ ) may be substituted with a group selected from alkyl and carbonyl,
B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, which are 5-membered or 6-membered monocycles or composed of two 5-membered or 6-membered monocycles Bicyclic,
q is an integer of 0 to 7,
The groups G ₃ may be the same or different and, independently of one another, (C ₁ -C ₆ ) alkyl, halogen, CN, NO ₂ , CF ₃ , OCF ₃ , — (CH ₂ ) _k NR ₁₃ R ₁₄ , — _{N (R 13) C (=} O) R 14, -N (R 13) C (= O) OR 14, -N (R 13) SO 2 R 14, -N (SO 2 R 13) 2, -OR ₁₃ , —S (O) _k1 R ₁₃ , —SO ₂ —N (R ₁₃ ) — (CH ₂ ) _{k 2} —NR ₁₄ R ₁₅ , — (CH ₂ ) _k SO ₂ NR ₁₃ R ₁₄ , —X ₄ (CH _{2) k C (= O)} OR 13, - (CH 2) k C (= O) OR 13, -C (= O) O- (CH 2) k2 -NR 13 R 14, -C (= O) O— (CH ₂ ) _k2 —C (═O) OR ₁₆ , —X ₄ (CH ₂ ) _k C (═O) NR ₁₃ R ₁₄ , — (CH ₂ ) _k C (═O) NR ₁₃ R ₁₄ , Selected from —R ₁₇ —C (═O) OR ₁₃ , —X ₅ —R ₁₈ , and —C (═O) —R ₁₉ —NR ₁₃ R ₁₄ , where:
X ₄ represents a group selected from an oxygen atom, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group,
k is an integer of 0 to 3,
k1 is an integer of 0 to 2,
k2 is an integer of 1 to 4,
R ₁₃ , R ₁₄ and R ₁₅ may be the same or different and are independently of each other selected from hydrogen and (C ₁ -C ₆ ) alkyl;
R ₁₆ is (C ₁ -C ₆ ) alkyl, —R ₁₉ —NR ₁₃ R ₁₄ , —R ₁₉ —NR ₁₃ —C (═O) —R ₁₉ —NR ₁₄ R ₁₅ , and —C (═O) From O—R ₁₉ —NR ₁₃ R ₁₄ (R ₁₉ represents a linear or branched (C ₁ -C ₆ ) alkylene group, and R ₁₃ , R ₁₄ and R ₁₅ are as defined above). Represents the selected group,
R ₁₇ represents a (C ₃ -C ₆ ) cycloalkyl group,
X ₅ represents a single bond, —CH ₂ —, an oxygen atom, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group. Represents a group selected from
R ₁₈ is
5- or 6-membered monocyclic aryl, heteroaryl, (C ₁ -C ₆ ) alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and —C (═O) OR ₇ (R ₇ is hydrogen or ( C ₁ -C ₆ ) representing alkyl) one or more selected from the same or different, optionally substituted by independent groups, and 5- or 6-membered monocyclic cycloalkyl, Heterocycloalkyl, (C ₁ -C ₆ ) alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and —C (═O) OR ₇ (R ₇ is hydrogen or (C ₁ -C ₆ ) Represents a group selected from those optionally substituted by one or more groups which may be the same or different, selected from alkyl. ]
Represents a group selected from:
M is an integer from 0 to 7;
The radicals R ₂ may be the same or different and, independently of one another, (C ₁ -C ₆ ) alkyl, halogen, —CN, NO ₂ , SCF ₃ , —CF ₃ , —OCF ₃ , —NR ₇ R _{8 , -OR 8, -SR 8, -SOR} 8, -SO 2 R 8, - (CH 2) k SO 2 NR 7 R 8, -X 7 (CH 2) k C (= O) OR 8, - ( _{CH 2) k C (= O} ) oR 8, -X 7 (CH 2) k C (= O) NR 7 R 8, - (CH 2) k C (= O) NR 7 R 8, and -X ₈ is selected from -R _20, wherein:
X ₇ represents a group selected from oxygen, sulfur optionally substituted by 1 or 2 oxygen atoms, and hydrogen or nitrogen substituted by a (C ₁ -C ₆ ) alkyl group;
k is an integer of 0 to 3,
R ₇ and R ₈ may be the same or different and are independently of each other selected from hydrogen and (C ₁ -C ₆ ) alkyl;
X ₈ is a single bond, —CH ₂ —, an oxygen atom, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group Represents a group selected from
R ₂₀ is 5-membered or 6-membered monocyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, which is 1 or selected from (C ₁ -C ₆ ) alkyl, halogen, hydroxy, and amino Optionally substituted by an identical or different group, and when the ring is a heterocycle, it comprises 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur . }
The compound, its racemate, its isomer, its N-oxide, and its pharmaceutically acceptable salts.

According to a first aspect, the present invention is a compound of formula (I) comprising:
G ₂ is C═O, _C═S , S (O) _n1 (n1 represents an integer of 0 to 2), or formula (i / c):

[Where:
The carbon atom having the number 1 is attached to the bicyclic ring of the compound of formula (I) and Y ₁ is selected from oxygen, sulfur, —NH and —N (C ₁ -C ₆ ) alkyl. And Y ₂ represents a group selected from oxygen, sulfur, —NH and —N (C ₁ -C ₆ ) alkyl. ]
Represents a group selected from:
X ₁ , X ₂ , X ₃ , G ₁ , n, Z ₁ , A, R ₁ , m and R ₂ are as defined in formula (I),
Relates to compounds.

According to a second aspect, the present invention is a compound of formula (I) comprising:
G ₂ represents a carbon-carbon triple bond;
n represents an integer of 1 to 6;
X ₁ , X ₂ , X ₃ , G ₁ , Z ₁ , A, R ₁ , m and R ₂ are as defined above,
Relates to compounds.

According to a third aspect, the present invention is a compound of formula (I) comprising:
G ₂ represents a carbon-carbon triple bond;
n is 0;
Z ₁ is not present;
A represents a group selected from heteroaryl, cycloalkyl, and heterocycloalkyl, and these rings are 5-membered or 6-membered monocycles, or bicycles composed of two 5-membered or 6-membered monocycles Is;
X ₁ , X ₂ , X ₃ , G ₁ , R ₁ , m and R ₂ are as defined above,
Relates to compounds.

According to a fourth aspect, the present invention is a compound of formula (I) comprising:
G ₂ represents a carbon-carbon triple bond;
n is 0;
Z ₁ is not present;
A represents a phenyl group;
R ₁ is a hydrogen atom, or formula (i / d):

[Where:
p is an integer of 0 to 8,
Z ₂ represents —CR ₁₁ R ₁₂ , and R ₁₁ and R ₁₂ may be the same or different, and independently of each other, hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, trihalogeno (C ₁ -C ₆ ) Represents a group selected from alkyl, halogen, amino, —OR ₇ , —SR ₇ and —C (═O) OR _{7, where} R ₇ represents hydrogen or (C ₁ -C ₆ ) alkyl, and p Is greater than or equal to ₂ , the hydrocarbon chain Z ₂ can contain 1 or 2 isolated or conjugated multiple bonds, and / or
When n is greater than or equal to 2, one of the —CR ₁₁ R ₁₂ is oxygen, S (O) _n1 (n1 is as defined above), —NH, —N (C _1- C ₆ ) may be substituted with a group selected from alkyl and carbonyl,
B represents a phenyl group;
q is an integer of 1 to 7,
The groups G ₃ may be the same or different and independently of each other —— (CH ₂ ) _k NR ₁₃ R ₁₄ , —N (R ₁₃ ) C (═O) OR ₁₄ , —N (R ₁₃ ) SO ₂ R ₁₄ , —N (SO ₂ R ₁₃ ) ₂ , —S (O) _k1 R ₁₃ , —SO ₂ —N (R ₁₃ ) — (CH ₂ ) _{k 2} —NR ₁₄ R ₁₅ , — (CH ₂ ) _k SO ₂ NR ₁₃ R ₁₄ , —X ₄ (CH ₂ ) _k C (═O) OR ₁₃ , — (CH ₂ ) _k C (═O) OR ₁₃ , —C (═O) O— (CH ₂ ) _{k 2} —NR ₁₃ R ₁₄ , —C (═O) O— (CH ₂ ) _{k 2} —C (═O) OR ₁₆ , —X ₄ (CH ₂ ) _k C (═O) NR ₁₃ R ₁₄ , — (CH ₂ ) _k C (═O) NR ₁₃ R ₁₄ , —R ₁₇ —C (═O) OR ₁₃ , —X ₅ —R ₁₈ , —C (═O) —R ₁₉ —NR ₁₃ R ₁₄ and —X ₆ —R ₂₁ Where is selected from:
X ₄ represents a group selected from an oxygen atom, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group,
k is an integer of 0 to 3,
k1 is an integer of 1 to 2,
k2 is an integer of 1 to 4,
R ₁₃ , R ₁₄ and R ₁₅ may be the same or different and are independently of each other selected from hydrogen and (C ₁ -C ₆ ) alkyl;
R ₁₆ is (C ₁ -C ₆ ) alkyl, —R ₁₉ —NR ₁₃ R ₁₄ , —R ₁₉ —NR ₁₃ —C (═O) —R ₁₉ —NR ₁₄ R ₁₅ , and —C (═O) From O—R ₁₉ —NR ₁₃ R ₁₄ (R ₁₉ represents a linear or branched (C ₁ -C ₆ ) alkylene group, and R ₁₃ , R ₁₄ and R ₁₅ are as defined above). Represents the selected group,
R ₁₇ represents a (C ₃ -C ₆ ) cycloalkyl group,
X ₅ represents a single bond, —CH ₂ —, an oxygen atom, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group. Represents a group selected from
R ₁₈ represents heteroaryl, cycloalkyl, heterocycloalkyl, these groups are 5-membered or 6-membered monocycles or bicyclics composed of two 5-membered or 6-membered monocycles, (C ₁ -C ₆₎ alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and _{-C (= O) oR 7 (} R 7 is hydrogen or (C ₁ -C ₆₎ alkyl) is selected from One or more of the same or different, which may be substituted by groups independent of each other,
X ₆ represents a group selected from —CH ₂ —, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group. Represent,
R ₂₁ is a phenyl group and is (C ₁ -C ₆ ) alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and —C (═O) OR ₇ (R ₇ is hydrogen or (C ₁ -C _6). ) Represents an alkyl group) and may be substituted by one or more of the same or different groups and independent of each other. ]
And X ₁ , X ₂ , X ₃ , G ₁ , m and R ₂ are as defined in formula (I),
Relates to compounds.

Substituent R _{1, which} is preferred according to the invention, has the formula (i / d):

[Wherein Z ₂ , p, B, G ₃ and q are as defined for the compound of formula (I). ]
It is the basis of.
More particularly, the substituent R _{1, which} is preferred according to the present invention, has the formula (i / d):

[Wherein Z ₂ represents a group —CR ₁₁ R ₁₂ , R ₁₁ and R ₁₂ each represent a hydrogen atom, and p, B, G ₃ , and q are defined in the compound of formula (I) Street. ]
It is the basis of.

More particularly, the substituent R _{1, which} is preferred according to the present invention, has the formula (i / d):

[Wherein p is 1 and Z ₂ , B, G ₃ , and q are as defined in the compound of formula (I). ]
It is the basis of.

More particularly, the substituent R _{1, which} is preferred according to the present invention, has the formula (i / d):

[Wherein B represents a phenyl group, q is equal to 0 or 1 and G ₃ is present when —OR ₁₃ , halogen, —S (O) _k1 R ₁₃ , and — (CH ₂ ) _k C (═O) OR ₁₃ (R ₁₃ represents a hydrogen atom or a (C ₁ -C ₆ ) alkyl group), k is 0, k1 is 2, and Z ₂ and p are as defined for the compound of formula (I). ]
It is the basis of.

The present invention relates to a compound of formula (I), wherein G ₁ represents a group of formula (i / a), wherein R ₄ represents a hydrogen atom or a methyl group, or G ₁ represents formula (i / a). b), wherein R ₄ and R ₅ are identical and each represents a hydrogen atom or a methyl group, and R ₆ represents a hydrogen atom or a methyl group, and X ₁ , X ₂ , X ₃ , It also relates to compounds wherein G ₂ , Z ₁ , n, m and R ₂ are as defined in formula (I).

Preferred compounds of the invention are those wherein X ₁ represents a group —CR ₃ , wherein R ₃ represents a hydrogen atom, X ₂ represents a nitrogen atom or a group —CR ₃ , wherein R ₃ represents a hydrogen atom. And a compound of formula (I) in which X ₃ represents a group —CR ₃ , where R ₃ represents a hydrogen atom.

Other preferred compounds of the invention are those wherein G ₂ represents a carbon-carbon triple bond or represents a group of formula (i / c), wherein Y ₁ represents an oxygen atom and Y ₂ represents a group —NH Represents a compound.
More preferred compounds of the invention are those wherein Z ₁ represents —CR ₉ R ₁₀ , R ₉ and R ₁₀ each represent a hydrogen atom and n is 1.

Particularly preferred compounds of the invention are those in which A represents a group selected from phenyl or pyridyl, m is 0 or 1, and R ₂ represents a (C ₁ -C ₆ ) alkoxy group or a hydrogen atom. is there.

More preferably, the present 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-carboxylic acid 4-methoxy-benzylamide, hydrochloride,
3- (4-methoxy-benzyl) -1-methyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 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-1,4-dihydro-2H-quinazolin-3-ylmethyl] -benzoic acid,
4- [6- (4-methoxy-benzylcarbamoyl) -1-methyl-4-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] -benzoic acid methyl ester,
4- [6- (4-methoxy-benzylcarbamoyl) -1-methyl-4-oxo-1,4-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,
4-oxo-3- [4- (pyrrolidine-1-sulfonyl) -benzyl] -3,4-dihydro-quinazoline-6-carboxylic acid 4-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] pyrimidine-6-carboxylic acid 3-methoxy-benzylamide, and 3- (3-fluoro-benzyl ) -4-Oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 4-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, and 3- (3,4- Dihydro-benzyl) -4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide.

More specifically, the present invention also relates to the following compounds of formula (I):
3- (4-fluorobenzyl) -6- (3-phenyl-prop-1-ynyl) -3H-quinazolin-4-one,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -methyl benzoate,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
3- (4-fluorobenzyl) -6- (3-phenyl-prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
4- [6- (3-phenyl-prop-1-ynyl) -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -methyl benzoate;
4- [6- (3-phenyl-prop-1-ynyl) -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -benzoic acid,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
4- {6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzamide, and 3-[(3,5-difluoro-4-hydroxy) -benzyl] -6- (3-Phenyl-prop-1-ynyl) -3H-quinazolin-4-one.

Further preferred compounds are
4- [6- (3-imidazol-1-yl-prop-1-ynyl) -4-oxo-4H-quinazolin-3-ylmethyl] -benzoic acid,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzenesulfonamide,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzonitrile,
3- (3-chloro-benzyl) -6- (4-phenyl-but-1-ynyl) -3H-quinazolin-4-one,
3- (3-chloro-benzyl) -6- (3-phenyl-prop-1-ynyl) -3H-quinazolin-4-one,
4- [4-oxo-6- (3-pyrazol-1-yl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
6- (3-phenyl-prop-1-ynyl) -3- [4- (1H-tetrazol-5-yl) -benzyl] -3H-quinazolin-4-one,
3- (3,4-dihydro-benzyl) -6- [3- (pyridin-4-yloxy) -prop-1-ynyl] -3H-quinazolin-4-one,
3- (3,4-dihydro-benzyl) -6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
N- {4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -phenyl} -acetamide,
3- (3,4-difluoro-benzyl) -6- (3-phenyl-prop-1-ynyl) -3H-quinazolin-4-one,
3- (4-acetyl-benzyl) -6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
6- (3-Phenyl-prop-1-ynyl) -3-pyridin-4-ylmethyl-3H-quinazolin-4-one, and 6- [3- (4-Methoxy-phenyl) -prop-1-ynyl] -3-Pyridin-4-ylmethyl-3H-quinazolin-4-one.

  Most preferred are the compounds listed in the following table, which are mentioned later in the examples of the present application.

The optical isomers of these preferred compounds, their N-oxides, and pharmaceutically acceptable acid or base addition salts form the cumulative part of this invention.
The present invention also relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I) as an active ingredient together with one or more pharmaceutically acceptable excipients or carriers.

  Another aspect of the invention is a formula for the manufacture of a medicament intended for the treatment of diseases including therapies by inhibition of matrix metalloproteinases, more particularly type 13 matrix metalloproteinases. It also relates to the use of the compounds of (I).

  The present invention is a method of treating a living organism suffering from a disease, including therapies by inhibition of matrix metalloproteinases, and more particularly, type 13 matrix metalloproteinases. It also relates to a method comprising administering to a patient an effective amount of a compound of formula (I).

  Preferred treatment methods according to the present invention include arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, inflammatory bowel disease, psoriasis, multiple sclerosis, heart failure, atherosclerosis, asthma, chronic obstructive pulmonary disease Treatment of a disease selected from age-related macular degeneration and cancer.

  More particularly, the preferred method of treatment according to this invention is the treatment of a disease selected from arthritis, osteoarthritis, and rheumatoid arthritis.

Detailed Description of the Invention

The compound provided by this invention is a compound defined by formula (I). In formula (I), the following should be understood:
A (C ₁ -C ₆ ) alkyl group represents a linear or branched group containing from 1 to 6 carbon atoms, and examples of such groups are not intended to impose limitations, but methyl Ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl,
A (C ₂ -C ₆ ) alkenyl group represents a linear or branched group containing 2 to 6 carbon atoms and one or more double bonds, examples of such groups are: Without limitation, vinyl, allyl, 3-buten-1-yl, 2-methyl-buten-1-yl, hexenyl,
A (C ₂ -C ₆ ) alkynyl group represents a linear or branched group containing 2 to 6 carbon atoms and one or more triple bonds, examples of such groups being limited Ethynyl, propynyl, 3-butyn-1-yl, 2-methyl-butyn-1-yl, hexynyl,
(C ₁ -C ₆ ) alkoxy group means the above alkyl group bonded through an oxygen atom, and examples of such compounds are not intended to be limiting, but include methoxy, ethoxy, n- Propyloxy, tert-butyloxy,
Mono (C ₁ -C ₆ ) alkylamino represents an amino group substituted by one (C ₁ -C ₆ ) alkyl group as defined above, and examples of such groups are not intended to be limiting. Not methylamino, isobutylamino, ethylamino,
Di (C ₁ -C ₆ ) alkylamino represents an amino group substituted by two (C ₁ -C ₆ ) alkyl groups as defined above, and each alkyl group may be the same or different, Examples of such groups include, but are not limited to, dimethylamino, diethylamino,
An aryl group represents an aromatic monocyclic or bicyclic ring system containing 5 to 10 carbon atoms, in which case one ring is aromatic and the other ring is aromatic. However, it may be partially hydrogenated and examples of such groups include, but are not limited to, phenyl, naphthyl, indenyl, benzocyclobutenyl,
A heteroaryl group represents an aryl group as described above wherein 1 to 4 carbon atoms are replaced by 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, examples of such groups are limited Although not reminiscent, furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, benzodioxolyl, benzodioxylyl, benzo [1,2,5] Thiadiazolyl, benzo [1,2,5] oxadiazolyl,
Cycloalkyl groups represent monocyclic or bicyclic systems containing 3 to 10 carbon atoms, which are partially unsaturated without saturation or aromaticity, examples of such groups are , But not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl,
A heterocycloalkyl group, as defined above, represents a cycloalkyl group in which 1-4 carbon atoms are replaced by 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;
Bicycle represents two fused monocycles, and a trihalogeno (C ₁ -C ₆ ) alkyl group represents an alkyl group as defined above containing a trihalogeno group, examples of such groups include Not praise, but trifluoromethyl, 2,2,2-trifluoroethyl,
A (C ₁ -C ₇ ) acyl group represents an alkyl or aryl group as defined above attached through a carbonyl group, and examples of such groups are not intended to imply limitations, but include acetyl , Ethylcarbonyl, benzoyl,
A multiple bond represents a double bond or a triple bond,
A halogen atom means fluoro, chloro, bromo or iodo;
Optical isomers refer to racemates, enantiomers and diastereomers.

The invention also relates to pharmaceutically acceptable salts of the compounds of formula (I). A summary of pharmaceutically acceptable salts is found in J. Pharm. Sci., 1977, 66, 1-19.
A pharmaceutically acceptable acid salt refers to a non-toxic salt derived from an inorganic or organic acid. Among them, the acid salts, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, citric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malon can be mentioned without limitation. Acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphenic acid, benzoic acid, toluenesulfonic acid and the like. Pharmaceutically acceptable base salt means a non-toxic salt derived from an inorganic or organic base. Among them, mention may be made of, without limitation, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, tert-butylamine, dibenzylethylenediamine, piperidine, pyrrolidine, benzylamine, 4 Grade ammonium hydroxide and the like.

This invention is a process for the preparation of a compound of formula (I), comprising:
Formula (II):

Wherein X ₁ , X ₂ , X ₃ and Y ₁ have the same definition as the compound of formula (I), and T represents a (C ₁ -C ₆ ) alkyl group. ]
Is used as a starting material,
The compound of formula (II) is represented by formula (III):

[Wherein Z ₁ , Y ₂ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
And the acid function in the presence of diisopropylethylamine and a solvent by activating with an activating agent to give a compound of formula (IV):

[Wherein, X ₁ , X ₂ , X ₃ , Y ₁ , T, Z ₁ , Y ₂ , R ₂ , A, n and m are as defined above]. ]
Produces a compound of
Then, a compound the ester group of the compound was obtained after being hydrolyzed formula (IV) is a base, the general formula R ₁ -NH ₂ R ₁ is defined as in the compounds of formula (I) Treated with an activator in the presence of a primary amine to give a compound of formula (V):

[Wherein, X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Z ₁ , R ₂ , R ₁ , A, n and m are as defined above]. ]
Produces a compound of
The compound of formula (V) is
Formula (I / a), which is a special case of a compound of formula (I), treated under heating conditions with triethyl orthoformate:

[Wherein, X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Z ₁ , R ₂ , R ₁ , A, n and m are as defined above]. ]
Or a compound of
Under heating conditions in the presence of acid, formula (VI):

[Wherein R ₄ has the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) treated with a compound of formula (I / b):

[Wherein, X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Z ₁ , R ₂ , R ₁ , R ₄ , A, n and m are as defined above]. ]
Or a compound of
Under basic conditions, formula (VII):

[Wherein R ₄ and R ₅ have the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) treated with a compound of formula (I / c):

[Wherein, X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Z ₁ , R ₂ , R ₁ , R ₄ , R ₅ , A, n and m are as defined above]. ]
Produces a compound of
Optionally, the compound of formula (I / c) is a hydride and a compound of formula (VIII):

[Wherein R ₆ has the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I), treated in the presence of a compound of formula (I / d):

[Wherein X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Z ₁ , R ₂ , R ₁ , R ₄ , R ₅ , R ₆ , A, n and m are as defined above] is there. ]
A method of producing a compound of
Compounds of formula (I / a), (I / b), (I / c) and (I / d) constitute several compounds of the present invention, which, if appropriate, are conventional Purified according to conventional purification techniques, if appropriate separated into their different isomers according to conventional separation techniques, and where appropriate to their addition salts with pharmaceutically acceptable acids or bases. Or it relates to the process of conversion to their N-oxides.

The present invention is a process for preparing a compound of formula (I) comprising:
Formula (X):

[Wherein X ₁ , X ₂ , and X ₃ have the same definition as the compound of formula (I), and Hal represents a halogen atom. ]
Is used as a starting material,
A compound of formula (X) is treated with a derivative of phosgene in a first step to give a compound of formula (XI):

[Wherein X ₁ , X ₂ , X ₃ and Hal are as defined above. ]
Produces a compound of
Compound of formula (XI), with a base medium, R ₁ to have been treated with a primary amine of general formula R ₁ -NH ₂ having the same definition as the compound of Formula (I), Formula (XII):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and Hal are as defined above. ]
Produces a compound of
The compound of formula (XII) is
Treated with triethyl orthoformate under heating conditions to give the formula (XIII / a):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and Hal are as defined above. ]
Or a compound of
Under heating conditions in the presence of acid, formula (VI):

[Wherein R ₄ has the same definition as the compound of formula (I). ]
Treated with a compound of formula (XIII / b):

[Wherein, X ₁ , X ₂ , X ₃ , Hal, R ₁ and R ₄ are as defined above. ]
Or a compound of
Under basic conditions, formula (VII):

[Wherein R ₄ and R ₅ have the same definition as the compound of formula (I). ]
Treated with a compound of formula (XIII / c):

[Wherein, X ₁ , X ₂ , X ₃ , Hal, R ₁ , R ₄ , and R ₅ are as defined above. ]
Produces a compound of
Optionally, the compound of formula (XIII / c) is a hydride and a compound of formula (VIII):

[Wherein R ₆ has the same definition as the compound of formula (I), and Hal is a halogen atom. ]
A specific case of a compound of formula (I), treated in the presence of a compound of formula (XIII / d):

[Wherein, X ₁ , X ₂ , X ₃ , Hal, R ₁ , R ₄ , R ₅ and R ₆ are as defined above. ]
Produces a compound of
All compounds of formula (XIII / a), (XIII / b), (XIII / c) and (XIII / d) are represented by formula (XIII / e):

[Wherein X ₁ , X ₂ , X ₃ , Hal, R ₁ and G ₁ are as defined in the compound of formula (I). ]
Composed of
A compound of formula (XIII / e) is prepared under the conditions of palladium catalyzed alkynylation:

[Wherein Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) treated with a compound of formula (I / e):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ , G ₁ , Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
A method of producing a compound of
Compounds of formula (I / e) constitute several compounds of the invention, which are purified according to conventional purification techniques, where appropriate, and where appropriate, conventional separation techniques. And, where appropriate, also relates to a process which is converted to their addition salts or to their N-oxides with pharmaceutically acceptable acids or bases.

  Another method for obtaining a compound of formula (XIII / a) from a compound of formula (XI) is described in the following scheme 1:

In the formula, X ₁ , X ₂ , X ₃ , R ₁ and Hal are as defined above. In the first step, a compound of formula (XI) is treated with an aqueous solution of ammonium hydroxide to produce a compound of formula (XI / a), which is a catalyst such as para-toluenesulfonic acid (PTSA). Treated with triethyl orthoformate in the presence of a quantity of acid. Resulting 3H- quinazolin-4-one (XI / b) is, in a basic medium, R ₁ to are as defined in compounds of formula (I) and the compound of the formula R ₁ -Hal in which Hal represents halogen To form a compound of formula (XIII / a).

The present invention is a process for preparing a compound of formula (I) comprising:
Formula (XIII / e):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and G ₁ are as defined in the compound of formula (I), and Hal is a halogen atom. ]
Is used as a starting material,
A compound of formula (XIII / e) is prepared in the presence of dichlorobis (triphenylphosphine) palladium, copper iodide, and N, N′-diisopropylethylamine in dimethylformamide:

[Wherein Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) condensed with a compound of formula (I / e):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ , G ₁ , Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
It also relates to a process for producing the compound.

The present invention is a process for preparing a compound of formula (I) comprising:
Formula (XIII / e):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and G ₁ are as defined in the compound of formula (I), and Hal is a halogen atom. ]
Is used as a starting material,
A compound of formula (XIII / e) is reacted with carbon monoxide in an alkaline medium in the presence of a protic solvent such as methanol and a catalytic amount of palladium to produce a compound of formula (XVI):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and G ₁ are as defined in the compound of formula (I). ]
Produces a compound of
A compound of formula (XVI) is hydrolyzed in a basic medium to give formula (XVII):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and G ₁ are as defined in the compound of formula (I). ]
Produces a compound of
A compound of formula (XVII) is synthesized in the presence of Mukayama reagent in a basic medium, formula (XVIII):

[Wherein Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) condensed with a compound of formula (I / f):

[Wherein X ₁ , X ₂ , X ₃ , Z ₁ , R ₂ , R ₁ , A, n and m are as defined above]. ]
A method of producing a compound of
Compounds of formula (I / f) constitute several compounds of the invention, which are purified according to conventional purification techniques, where appropriate, and where appropriate, conventional separation techniques. And, where appropriate, also relates to a process which is converted to their addition salts or to their N-oxides with pharmaceutically acceptable acids or bases.

The present invention is a process for preparing a compound of formula (I) comprising:
Formula (XIX):

[Wherein Hal represents a halogen atom. ]
Is used as a starting material,
A compound of formula (XIX) is heated in the presence of formamidine acetate in a polar solvent such as 2-methoxyethane-1-ol to produce a compound of formula (XX):

[Wherein Hal is as defined above. ]
Produces a compound of
A compound of formula (XX) is treated with a compound of formula R ₁ -Hal in a basic medium, wherein R ₁ is as defined in the compound of formula (I) and Hal represents a halogen atom, to give a compound of formula (XXI ):

[Wherein Hal and R ₁ are as defined above. ]
Produces a compound of
A compound of formula (XXI) is reacted with carbon monoxide in a basic medium in the presence of an alcohol solvent such as methanol and a catalytic amount of palladium such as PdCl ₂ (dppf) to give a compound of formula (XXII) :

[Wherein R ₁ is as defined above. ]
Produces a compound of
A compound of formula (XXII) is prepared in the presence of trimethylaluminum in formula (XVIII):

[Wherein Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) condensed with a compound of formula (I / g):

[Wherein Z ₁ , R ₂ , R ₁ , A, n and m are as defined above. ]
A method of producing a compound of
The compounds of formula (I / g) constitute several compounds of the invention, which are purified according to conventional purification techniques, where appropriate, and where appropriate, conventional separation techniques. And, where appropriate, also relates to a process which is converted to their addition salts or to their N-oxides with pharmaceutically acceptable acids or bases.

The compounds of the invention that exist in the form of a mixture of diastereomers are isolated in pure form using conventional separation techniques such as chromatography.
As described above, the compounds of formula (I) of the present invention are matrix metalloproteinase inhibitors, more particularly inhibitors of the enzyme MMP-13.

  In this regard, their use is recommended for the treatment of diseases or conditions including therapy with MMP-13 inhibitors. By way of example, the compounds of the present invention can be used in any medical condition in which extracellular matrix tissue destruction occurs, most particularly arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, inflammatory bowel disease, psoriasis, It can be recommended for the treatment of medical conditions such as multiple sclerosis, heart failure, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration, and cancer.

  The present invention relates to at least one compound of formula (I), isomers thereof, N-oxides thereof, or addition salts thereof with pharmaceutically acceptable acids or bases, alone or as an active ingredient. It also relates to a pharmaceutical composition comprising an inert pharmaceutically acceptable non-toxic excipient or carrier.

  Among the pharmaceutical compositions according to the invention, suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, intravaginal, rectal, nasal, translingual, sublingual, intraocular or respiratory administration Especially the ones can be mentioned.

  Pharmaceutical compositions according to the invention for parenteral injection are in particular aqueous and non-aqueous sterile solutions, dispersions, suspensions and emulsions, as well as solutions for injection or suspensions. Sterile powder is also included.

  Pharmaceutical compositions according to the invention for oral administration in solid form include in particular tablets or dragees, sublingual tablets, sachets, gelatin capsules and granules, oral in liquid form, nasal, For sublingual or intraocular administration, inter alia emulsions, solutions, suspensions, drops, syrups and aerosols are included.

Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories, and for transdermal administration are powders, aerosols, creams, gels and patches.
The pharmaceutical compositions listed so far are examples of the present invention and do not limit the present invention.

  Diluents, solvents, preservatives, wetting agents, emulsifiers, dispersants, binders, swelling agents, disintegrants, retarders, lubricants, absorption, among pharmaceutically acceptable inert non-toxic excipients or carriers Agents, suspending agents, coloring agents, fragrances can be mentioned as non-limiting examples.

  Useful doses will vary according to the age and weight of the patient, the route of administration, the pharmaceutical composition used, the nature and severity of the disorder, and the administration of any related treatment. Doses range from 2 mg to 1 g per day for one or more administrations. The compositions are prepared by methods routine to those of ordinary skill in the art and generally include 0.5-60% by weight of active drug substance (compound of formula (I)) and 40-99.5% by weight of pharmaceutically. It comprises an acceptable excipient or carrier.

The following examples are illustrative of the present invention and are not intended to limit the present invention.
The starting materials used are substances which are known or are prepared according to known procedures. Various preparation examples provide synthetic intermediates that are useful in the preparation of the compounds of the invention. Some of these intermediates are novel compounds.

The structures of the compounds described in the examples and preparation examples were determined according to the usual spectroscopic method (infrared, nuclear magnetic resonance, mass spectrum).
In production examples and examples,
DMF means dimethylformamide,
THF means tetrahydrofuran,
DMSO means dimethyl sulfoxide,
TOTU means O- (ethoxycarbonyl) cyanomethylamino] -N, N, N ′, N′-tetramethyluronium fluoroborate
DIPEA means diisopropylethylamine.

Production Example 1: 4-Amino-3-[(4-methoxy) -benzylcarbamoyl ] -1-carboxylic acid 4-methoxy-benzylamide Step 1: 6.3 g (150 mmol) of 4-amino-isophthalic acid in LiOH.H ₂ O is added to a stirred solution of 15.7 g (75 mmol) methyl 4-amino-isophthalate in 300 ml dioxane and 1200 ml water. The reaction mixture is heated to 100 ° C. for 1 hour, cooled and acidified to pH = 1 by the addition of concentrated HCl. A precipitate is obtained, then filtered, washed and dried in vacuo to give 13 g (yield = 95.7%) of the desired compound.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 6.80 (d, 1H); 6.80-7.80 (bs); 7.80 (dd, 1H); 8.35 (s, 1H); 11.9-13.1 (bs).

  Step 2: 4-Amino-3-[(4-methoxy) -benzylcarbamoyl] -phenyl-1-carboxylic acid 4-methoxy-benzylamide

2.25 g (16.5 mmol) 4-methoxybenzylamine, 5.4 g (16.5 mmol) TOTU, and 5.4 ml (3.9 g, 30 mmol) DIPEA, 2.7 g (15 mmol) of step 1 Are added sequentially to a stirred solution of the compound obtained in 100 ml in DMF. The reaction mixture is stirred overnight at room temperature before the solvent is removed in vacuo. The crude mixture is taken up in dichloromethane and washed sequentially with HCl 1N and NaOH 1N. After separation by decantation, the organic layer is dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product is purified by chromatography and solidified from a mixture of dichloromethane and ether to give 3.1 g (yield = 49.3%) of the desired compound.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.70 (s, 6H); 4.35 (t, 4H); 6.70 (d, 1H); 6.80-6.90 (m, 6H); 7.20-7.30 (m, 4H ); 7.65 (dd, 1H); 8.10 (s, 1H); 8.45 (t, 1H); 8.75 (t, 1H).

Production Example 2: Methyl 4-{[2-amino-5- (4-methoxy-benzylcarbamoyl) -benzoylamino] -methyl} benzoate Step 1: 6-amino-N- (4-methoxy-benzyl) -isophthal Methyl acid

6.56 g (20 mmol) of TOTU and 2.6 ml (2.74 g, 20 mmol) of 4-methoxybenzylamine were converted to 4.2 g (18.1 mmol) of 4-amino-3-methylcarboxylate-1-phenylcarboxyl. To the stirred solution of acid in 150 ml anhydrous DMF. The mixture is cooled to 0 ° C. and 9.5 ml (7.02 g, 54.3 mmol) of DIPEA is added. The reaction mixture is stirred at room temperature overnight and concentrated in vacuo. The residue is taken up in 150 ml of dichloromethane and washed with 100 ml of a saturated solution of NaHCO ₃ . The organic layer is dried and concentrated under reduced pressure. After chromatography on silica gel, 3.5 g (yield = 62%) of the target compound is isolated.
TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.80
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.80 (s, 3H); 3.90 (s, 3H); 4.55 (d, 2H); 6.0-6.15 (bs, 2H); 6.15-6.30 (bs, 1H 6.65 (d, 1H); 6.90 (d, 1H); 7.25-7.30 (m, 2H); 7.80 (d, 1H); 8.25 (s, 1H).
Purity: HPLC = 98.5%.

  Step 2: 6-amino-N- (4-methoxy-benzyl) -isophthalamic acid

0.3 g (7 mmol) LiOH and H ₂ O are added to a stirred solution of 1.1 g (3.5 mmol) of the compound obtained in step 2 above in 10 ml dioxane and 40 ml water. The reaction mixture is refluxed for 2 hours, cooled and acidified to pH = 1 by addition of concentrated HCl. The obtained precipitate is filtered to obtain the target compound.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.70 (s, 3H); 4.35 (d, 2H); 6.75 (d, 1H); 6.85 (d, 2H); 7.20 (d, 2H); 7.75 ( dd, 1H); 8.30 (s1H); 8.65 (t, 1H).

  Step 3: 4-{[2-Amino-5- (4-methoxy-benzylcarbamoyl) -benzoylamino] -methyl} -methyl benzoate

The target compound was obtained according to the procedure described in Step 1 of Production Example 2 using the compound obtained in Step 2 above as the starting material and methyl 4- (aminomethyl) benzoate hydrochloride as the reactant. It is done. It is purified by chromatography on silica gel using a dichloromethane / ether mixture as eluent.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.70 (s, 3H); 3.85 (s, 3H); 4.40 (d, 2H); 4.50 (d, 2H); 6.70 (d, 1H); 6.80- 6.90 (m, 4H); 7.25 (d, 2H); 7.45 (d, 2H); 7.70 (dd, 1H); 7.95 (d, 2H); 8.15 (s, 1H); 8.45 (t, 1H); 8.90 (t, 1H).

Production Example 3: 3- (4-Fluorobenzyl) -6-iodo-3H-quinazolin-4-one Step 1: 6-iodo-1H-benzo [a] [1,3] oxazine-2,4-dione

To a suspension of 2-amino-5-iodobenzoic acid (4.9 g, 18.0 mmol) in H ₂ O (20 ml) and concentrated HCl (5 ml), dioxane (50 ml) is obtained, giving a clear solution. Add until. Neat diphosgene (5.95 g, 30.0 mmol) is added dropwise (with occasional cooling so that the solution does not boil) to give a white precipitate. After stirring for 10 minutes at room temperature, H ₂ O (about 100 ml) is added and the precipitate is filtered and washed with a large amount of H ₂ O. It is dried in vacuo to give the desired product (5.2 g, quantitative) as white crystals.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 6.93 (d, J = 8.6Hz, 1H), 8.00 (dd, J = 8.6,2.0Hz, 1H), 8.10 (d, J = 2.0Hz, 1H) , 11.8 (s, 1H);
MS (APCI), M / z 288.0 (M-1).

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

Neat 4-fluorobenzylamine (1.18 g, 9.45 mmol) is added dropwise to a 50 ° C. solution of the compound obtained in the previous step 1 (2.1 g, 7.27 mmol) in DMF (20 ml). . The reaction was stirred at room temperature for 10 minutes, during which time bubbling was observed (CO ₂ ) and TLC indicated the reaction was complete. The reaction contents are poured into a separatory funnel charged with CH ₂ Cl ₂ and H ₂ O. After separation, the organic layer is washed with H ₂ O (3 × 5 Oml) and brine (50 ml). It is dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a white solid, which is purified using flash chromatography to give the desired compound as a white solid (2.5 g, 93 %).
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 5.15 (d, J = 5.8Hz, 2H), 6.50 (s, 1H), 7.03 (m, 1H); 7.34 (m, 1H), 7.43 (d, J = 8.5Hz, 1H), 8.02 (m, 1H), 8.10 (s, 1H), 8.66 (d, j = 1.9Hz, 1H), 9.18 (t, J = 5.8Hz, 1H);
MS (APCI), M / z 371.0 (M + 1).

  Step 3: 3- (4-Fluorobenzyl) -6-iodo-3H-quinazolin-4-one

To a solution of the compound obtained in step 2 above (2.69 g, 7.27 mmol) in triethyl orthoformate, a catalytic amount of TsOH is added. The solution is refluxed for 5 hours and cooled to room temperature. After removing all volatiles under reduced pressure, the residue is purified using flash chromatography to give the desired quinazolinone as a brown solid. Upon grinding, the target compound is obtained as a white solid (1.56 g, 58%).
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 5.15 (s, 2H), 7.03 (m, 1H); 7.34 (m, 1H), 7.43 (d, J = 8.5Hz, 1H), 8.02 (m, 1H), 8.10 (s, 1H), 8.66 (d, J = 1.9Hz, 1H);
MS (APCI), M / z 381.0 (M + 1).

Production Example 4: Methyl 4- (6-iodo-4-oxo-4H-quinazolin-3-ylmethyl-benzoate Step 1: 4-[(2-amino-5-iodo-benzoylamino) -methyl] -benzoic acid Methyl

To a 50 ° C. solution of the compound obtained in Step 1 of Production Example 3 (1.4 g, 4.84 mmol) in DMF (20 ml) was added 4-carbomethoxy-benzylamine hydrochloride (1.17 g, 5.8 mmol). ) Is added. The reaction was stirred at room temperature for 1 hour, during which time bubbling was observed (CO ₂ ) and TLC indicated complete reaction. The reaction contents are poured into a separatory funnel charged with CH ₂ Cl ₂ and H ₂ O. After separation, the organic layer is washed 3 times with H ₂ O to remove DMF. It is then washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the desired amide as a brown solid (2.0 g, quantitative).
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.31 (s, 3H), 4.36 (d, J = 5.9Hz, 2H), 6.55 (d, J = 8.6Hz, 1H), 6.59 (s, 2H) , 7.15 (m, 2H), 7.35 (m, 4H), 7.80 (d, J = 1.9Hz, 1H), 8.88 (t, J = 5.9Hz, 1H);
MS (APCI), M / z 411.0 (M + 1).

  Step 2: 4- (6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl) -methyl benzoate

To a solution of the compound obtained in the previous step 1 (2.0 g, 4.84 mmol) in triethyl orthoformate, a catalytic amount of TsOH is added. The solution is refluxed for 5 hours and cooled to room temperature. After removing all volatiles under reduced pressure, the residue is purified using flash chromatography to give the desired quinazolinone as a brown solid. Upon grinding, the target compound is obtained as a white solid (1.0 g, 50%).
NMR (CDCl ₃ ) ¹ Hδ (ppm): 3.31 (s, 3H), 5.26 (d, 2H), 7.48 (m, 4H), 7.90 (d, J = 6.8Hz, 2H), 8.10 (m, 1H) , 8.40 (d, J = 1.7Hz, 1H), 8.60 (d, J = 1.5Hz, 1H)
MS (APCI), M / z 421.3 (M + 1).

Production Example 5: 3- (4-Fluoro-benzyl) -6-iodo-3H-pyrido [3,4-d] pyrimidin-4-one Step 1: 6-iodo-1H-pyrido [3,4-d] [1,3] Oxazine-2,4-dione

To a suspension of 2-amino-5-iodo-isonicotinic acid (18.Ommol) in H ₂ O (20ml) and concentrated HCl (5ml), dioxane (50ml) is added until a clear solution is obtained. . Neat diphosgene (5.95 g, 30.0 mmol) is added dropwise (with occasional cooling so that the solution does not boil) and a precipitate is formed. After stirring at room temperature for 10 minutes, H ₂ O (100 ml) is added and the precipitate is filtered and washed with copious amounts of H ₂ O. The filtrate is dried under reduced pressure to obtain the target compound.

  Step 2: 5-amino-N- (4-fluoro-benzyl) -2-iodo-isonicotinamide

4-Fluorobenzylamine (9.45 mmol) is added dropwise to a 50 ° C. solution of the compound obtained in step 1 (7.27 mmol) in DMF (20 ml). The reaction was stirred at room temperature for 10 minutes, during which time bubbling was observed (CO ₂ ) and TLC indicated the reaction was complete. The reaction contents are poured into a separatory funnel charged with CH ₂ Cl ₂ and H ₂ O. After separation, the organic layer is washed with H ₂ O (3 × 5 Oml) and brine (50 ml). The organic layer is then dried (Na ₂ SO ₄ ), filtered, concentrated in vacuo, and the residue is optionally purified using flash chromatography on silica gel to give the desired compound. give.

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

  To a solution of the compound obtained in step 2 (7.27 mmol) in triethyl orthoformate, a catalytic amount of p-toluenesulfonic acid is added. The solution is refluxed for 5 hours and cooled to room temperature. After all volatiles are removed in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.

Production Example 6: 4- (6-Iodo-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl) -methyl benzoate Step 1: 4-{[(5-Amino-2-iodo -Pyridine-4-carbonyl) -amino] -methyl} -methyl benzoate

4-Carbomethoxy-benzylamine hydrochloride (1.17 g, 5.8 mmol) is added to a 50 ° C. solution of the compound obtained in Step 1 of Preparation Example 6 (4.84 mmol) in DMF (20 ml). . The reaction was stirred at room temperature for 1 hour, during which time bubbling was observed (CO ₂ evolution) and TLC indicated complete reaction. The reaction contents are poured into a separatory funnel charged with CH ₂ Cl ₂ and H ₂ O. After separating the layers, the organic layer is washed 3 times with H ₂ O to remove DMF. The organic layer is then washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the desired compound.

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

  To a solution of the compound obtained in step 1 (4.84 mmol) in triethyl orthoformate, a catalytic amount of TsOH is added. The solution is refluxed for 5 hours and cooled to room temperature. After all volatiles are removed in vacuo, the residue is purified using flash chromatography on silica gel to give the desired compound.

Production Example 7: 3- (4-Fluoro-benzyl) -4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid Step 1: 3- (4-Fluoro -benzyl) -4-oxo-3,4 -Methyl dihydro-quinazolinecarboxylate

2.0 g (5.27 mmol) of the compound prepared in Preparation 3 is dissolved in 50 ml of 1: 1 DMF: methanol, excess triethylamine, and catalytic amount of Pd (dppf) Cl ₂ . The reaction solution is poured into an autoclave and heated at 100 ° C. for 4 hours under a carbon monoxide atmosphere. The reaction is cooled to room temperature and filtered. The filtrate is concentrated in vacuo and the residue is purified on a silica gel column using 1: 1 hexane: EtOAc to give the desired product as a white solid (100%).

  Step 2: 3- (4-Fluoro-benzyl) -4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid

1.7 g (5.27 mmol) of the compound obtained in step 1 above is dissolved in 50 ml of 90% THF: 10% water. 10 equivalents of LiOH are added and the reaction solution is refluxed for 5 hours. The reaction solution is diluted with 100 ml water and concentrated HCl is used to make the pH of the solution acidic to 1.0. The solution is extracted with 200 ml EtOAc and the organic layer is washed with 2 × 100 ml water and 1 × 100 ml brine. The organic layer is dried over MgSO ₄ and concentrated to give 1.5 g of the desired product as a dull white solid.

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

  This compound is obtained according to the procedure described in Preparation Example 7, but the compound obtained in Step 1 of Preparation Example 3 is used, and 4-methanesulfonyl-benzyl is used instead of 4-fluorobenzylamine in Step 2. Amines are used.

Production Example 9: 3- [4- (Pyrrolidine-1-sulfonyl) -benzyl] -4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid

  This compound is obtained according to the procedure described in Preparation Example 7, but the compound obtained in Step 1 of Preparation Example 3 is used, and 4- (pyrrolidine-1) is used instead of 4-fluorobenzylamine in Step 2. -Sulfonyl) -benzylamine is used.

Production Example 10: 4- (6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl) -benzoic acid tert-butyl
Step 1: 2-amino-5-iodo-benzamide

2.0 g (6.90 mmol) of the compound obtained in Step 1 of Preparation 3 is dissolved in about 50 ml of DMF and an excess amount of aqueous ammonium hydroxide is added. After stirring for 10 minutes, the reaction solution is poured into 100 ml of water, acidified with conc. HCl and then extracted with 2 × 100 ml of EtOAc. The combined organic layers are then concentrated to give 1.8 g (100%) of the desired product as a dull white solid.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 6.50 (d, J = 8.8Hz, 1H), 6.68 (s, 2H), 7.12 (s, 1H), 7.33 (dd, J ₁ = 8.8Hz, J ₂ = 2.1Hz, 1H), 7.77 (d, J = 1.9Hz, 2H).

  Step 2: 6-iodo-3H-quinazolin-4-one

1.8 g (6.90 mmol) of the compound obtained in step 1 is suspended in 30 ml of triethyl orthoformate. A catalytic amount of p-toluenesulfonic acid is added and the suspension is refluxed for 3 hours. All volatiles are removed in vacuo and the residue is washed with 1: 1 dichloromethane: hexane to give 1.5 g (80%) of a dull white powder as the desired product.
MS (APCI), M / z 270.9 (M-1)
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 7.42 (d, J = 8.5Hz, 1H), 8.09 (dd, J ₁ = 8.5Hz, J ₂ = 2.2Hz, 1H), 8.09 (s, 1H) , 8.34 (d, J = 2.2Hz, 1H), 12.38 (broad s, 1H).

  Step 3: 4- (6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl) -benzoic acid tert-butyl

0.9 g (3.31 mmol) of the compound obtained in step 2 is dissolved in 50 ml of DMF. 1.18 g (3.64 mmol) of cesium carbonate and 0.986 g (3.64 mmol) of tert-butyl 4-bromomethyl-benzoate are added. The reaction is stirred at room temperature for 24 hours. Then 200 ml of EtOAc is added and washed with 3 × 100 ml of water. The organic layer is dried over MgSO ₄ and concentrated. The residue is purified on a silica gel column using dichloromethane: hexane increasing gradually from 4: 1 to 1: 1 ratio to give 0.97 g (62%) of white powder as the desired product.
MS (APCI), M / z 270.9 (M-1)
NMR (CDCl ₃ ) ¹ Hδ (ppm): 5.21 (s, 2H), 7.36 (d, J = 8.5Hz, 2H), 7.43 (d, J = 8.5Hz, 1H), 7.96 (dd, J ₁ = 6.6 Hz, J ₂ = 3.1 Hz, 2H), 8.01 (dd, J ₁ = 6.5 Hz, J ₂ = 2.1 Hz, 1H), 8.07 (s, 1H), 8.64 (d, J = 1.8 Hz, 1H).

Example 1: 3- (4-Methoxy-benzyl) -4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide

0.42 g (1.0 mmol) of the compound of Preparation Example 1 and 2.1 ml (1.85 g, 12.5 mmol) of triethyl orthoformate are stirred at 160 ° C. for 20 hours. After cooling, the resulting precipitate is filtered off and recrystallised from acetonitrile to give 0.180 g (yield = 42%) of the desired compound.
TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.46
NMR (DMSO-d ₆ ) ¹ Hδ (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, 1H); 8,25 (d, 1H); 8.65 (s, 1H) 8.70 (s, 1H); 9.25 (t, 1H)
IR: 3282, 1661, 1606, 1513, 1248, 1032, 841 cm ^-1
MP = 169 ° C
Purity: HPLC = 96.7%.

Example 2: 3- (4-Methoxy-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 Preparation 1, 1 ml of 6% HCl ethanol, and 103 μl (100 mg, 1 mmol) of acetylacetone are stirred and then refluxed overnight. After cooling, the resulting precipitate is filtered off and recrystallized from acetonitrile to give the desired compound.
TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.56
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 2.70 (s, 3H); 3.75 (s, 6H); 4.45 (d, 2H); 5.35 (s, 2H); 6.85-6.95 (m, 4H); 7.20-7.30 (m, 4H); 7.30-7.80 (bs, IH), 7.80 (d, 1H); 8.35 (d, 1H); 8.70 (s, 1H); 9.35 (t, 1H).
IR: 3282, 1702, 1648, 1634, 1547, 1512, 1250, 1178, 1035, 793 cm ⁻¹ .
MP = 208 ° C
Purity: HPLC = 98.9%.

Example 3: 3- (4-Methoxy-benzyl) -1-methyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide

To a stirred solution of 0.42 g (1 mmol) of the compound of Preparation Example 1 in 2 ml of methanol is added 75 μl (1 mmol) of formaldehyde. The resulting solution is refluxed for 1 hour. Then 820 μl of NaOH 2M solution is added and reflux is continued for 20 minutes. After cooling, water is added and the solution is extracted with ethyl acetate. The organic layer is decanted, dried and concentrated in vacuo. The crude product (0.32 g, 75 mmol) is dissolved in 3 ml of anhydrous DMF and stirred under an inert atmosphere. 35 mg (0.09 mmol) of NaH is added to this solution and the resulting yellow solution is stirred for 30 minutes at room temperature before 55 μl (125 mg, 0.9 mmol) of methyl iodide is added. After stirring for 30 minutes, the reaction mixture is treated as usual and chromatographed on silica gel (dichloromethane / ether) to give the desired compound.
NMR (DMSO-d ₆ ) ¹ Hδ (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, 1H); 8.35 (s, 1H); 8.90 (t, 1H)
IR: 1637, 1511, 1467, 1247, 1175 cm ^-1
MP = 182 ° C
Purity: HPLC = 95.6%.

Example 4: 3- (4-Methoxy-benzyl) -1,2,2-trimethyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide

5 mg of p-toluenesulfonic acid is added to a stirred solution of 0.42 g of the compound of Preparation Example 1 in 3 ml of acetone. The reaction mixture is stirred overnight at room temperature. This process is repeated to obtain a complete reaction. The solution is concentrated under reduced pressure and the crude product is methylated by addition of methyl iodide in the presence of NaH as described in Example 3. After chromatographic purification, the product obtained is crystallized in a mixture of dichloromethane and ether to give the desired compound.
TLC: CH ₂ Cl ₂ / acetone 90/10 Rf = 0.36
NMR (DMSO-d ₆ ) ¹ Hδ (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, 1H); 7.20-7.30 (m, 4H); 7.90 (d, 1H); 8.40 (s, 1H); 8.90 (t, 1H)
IR: 1638, 1608, 1511, 1499, 1299, 1249, 1174 cm ^-1
MP = 168 ° C
Purity: HPLC = 96.4%.

Example 5: 4- [6- (4-Methoxy-benzylcarbamoyl) -4-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid

This compound is obtained according to the procedure described in Step 1 of Example 3 using the compound obtained in Preparation Example 2 as a reaction substrate.
TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.10
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.70 (s, 3H); 4.35 (d, 2H); 4.60 (s, 2H); 4.70 (s, 2H); 6.75 (d, 1H); 6.85 ( d, 2H); 7.20-7.30 (m, 3H); 7.45 (d, 2H); 7.80 (d, 1H); 7.90 (d, 2H); 8.30 (s, 1H); 8.85 (t, 1H); 12.85 (bs, 1H)
IR: 3314, 1678, 1629, 1513, 1294, 1248 cm ^-1
MP = 270 ° C.
Purity: HPLC = 97.9%.

Example 6: 4- [6- (4-Methoxy-benzylcarbamoyl) -1-methyl-4-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] -methyl benzoate

This compound is obtained according to the procedure described in Step 2 of Example 3 using the compound obtained in Example 5 as the reaction substrate.
TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.70
NMR (DMSO-d ₆ ) ¹ Hδ (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, 1H); 8.90 (t, 1H)
IR: 3370, 1720, 1651, 1631, 1608, 1514, 1475, 1275, 1246, 1111 cm ^-1
MP = 175 ° C
Purity: HPLC = 94.5%.

Example 7: 4- [6- (4-Methoxy-benzylcarbamoyl) -1-methyl-4-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] -benzoic acid

This compound is obtained using the compound of Example 6 as a reaction substrate according to the procedure described in Step 2 of Preparation Example 5.
TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.35
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 2.85 (s, 3H); 3.70 (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); 7.95-8.00 (m, 3H); 8.40 (s, 1H); 8.90 (t, 1H); 12.90 (bs, 1H)
IR: 3540, 2740, 1709, 1637, 1513, 1476, 1313, 1245, 1173 cm ^-1
MP = 124 ° C
Purity: HPLC = 95.4%.

Example 8: 3- (4-Fluorobenzyl) -6- (3-phenyl-prop-1-ynyl) -3H-quinazolin-4-one

Compound of Production Example 3 (153 mg, 0.40 mmol) and benzylacetylenylstannane (prepared by adding n-BuLi to a -78 ° C solution of benzylacetylene and then deactivating the activity with tributyltin chloride) A catalytic amount of PdCl ₂ (Ph ₃ P) ₂ and CuI is added to the THF solution. The resulting suspension is refluxed for 1 hour and cooled to room temperature. After filtration and evaporation in vacuo, the residue is purified using flash chromatography to give the target compound as a white solid (80 mg, 54%).
NMR (CDCl ₃ ) ¹ Hδ (ppm): 3.87 (s, 2H), 5.15 (s, 2H), 7.15 (t, J = 8.3Hz, 1H), 7.26-7.43 (m, 5H), 7.62 (d, J = 8.3Hz, 1H), 7.77 (dd, J = 8.3,1.9 Hz, 1H), 8.08 (s, 1H), 8.39 (d, J = 1.9Hz, 1H);
MS (APCI), M / z 369.5 (M + 1).

Example 9: 4- [4-Oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -methyl benzoate

By adding n-BuLi to the −78 ° C. solution of the compound of Production Example 4 (165 mg, 0.39 mmol) and benzylacetylenylstannane (239 mg, 0.59 mmol, benzylacetylene), the activity is reduced with tributyltin chloride. A catalytic amount of Pd (PPh ₃ ) ₂ Cl ₂ and CuI is added to a THF solution with the one just prepared. The resulting suspension is refluxed for 1 hour. After filtration and evaporation under reduced pressure, the residue is purified using flash chromatography to give the target compound as a white solid.
NMR (CDCl ₃ ) ¹ Hδ (ppm): 3.85 (s, 2H), 3.89 (s, 3H), 5.23 (s, 2H), 7.40 (m, 5H), 7.80 (s, 1H), 8.00 (d, J = 8.3Hz, 2H), 8.40 (s, 1H)
MS (APCI), M / z 409.5 (M + I).

Example 10: 4- [4-Oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid
Step 1 : 4- (6-Iodo-4-oxo-4H-quinazolin-3-ylmethyl) -benzoic acid

LiOH (2.25 g, 53.6 mmol) is added to a solution of the compound of Preparation Example 4 (2.25 g, 5.36 mmol) in 10% H ₂ O THF. The reaction is stirred overnight at room temperature. After acidification using concentrated HCl, the reaction mixture is extracted with EtOAc. The organic layer is washed with water and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product is triturated using a hexane / EtOAc: 4/1 mixture to give 2.00 g of the desired compound as a white powder.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 5.23 (s, 2H), 7.40 (d, J = 8.3Hz, 2H), 7.47 (d, J = 8.6Hz, 1H), 7.87 (d, J = 8.1,2H), 8.1 (dd, J ₁ = 8.6Hz, J ₂ = 1.9Hz, 1H), 8.38 (d, J = 1.7Hz, 1H), 8.59 (s, 1H), 12.94 (br s, 1H)
MS (APCI), M / z 404.9 (M-1).

Step 2 : 4- [4-Oxo-6- (3-phenyl-prop-1-ynyl) -4H-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 was added diisopropylethylamine (0.381 g, 2.96 mmol), CuI (catalytic amount), 3-phenyl-1 Propine (0.120 g, 1.03 mmol) and Pd (PPh ₃ ) ₂ Cl ₂ (catalytic amount) are added. The reaction mixture is heated to 50 ° C. for 4 hours. The mixture is then diluted with 150 ml EtOAc and washed with 3 × 100 ml water, 1 × 100 ml brine. The organic layer is then dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure. The crude product is triturated with a mixture of hexane / EtOAc: 8/1 to give 225 mg of pure target compound as a pale yellow solid.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.91 (s, 2H), 5.23 (s, 2H), 7.23-7.43 (m, 9H), 7.66 (d, J = 8.3Hz, 1H), 7.83 ( dd, J ₁ = 8.6Hz, J ₂ = 1.7Hz, 1H), 7.87 (br s, 1H), 8.09 (d, J = 1.6Hz, 1H), 8.58 (s, 1H)
MS (APCI), M / z 395.1 (M + 1).

Example 11: 3- (4-Fluorobenzyl) -6- (3-phenyl-prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidin-4-one

Compound of Preparation Example 5 (0.40 mmol) and benzylacetylenylstannane (prepared by adding n-BuLi to a -78 ° C solution of benzylacetylene and then deactivating with tributyltin chloride) A catalytic amount of PdCl ₂ (Ph ₃ P) ₂ and CuI is added to the THF solution. The resulting suspension is refluxed for 1 hour and cooled to room temperature. After filtration and evaporation under reduced pressure, the residue is purified using flash chromatography on silica gel to give the desired compound.

Example 12: 4- [6- (3-Phenyl-prop-1-ynyl) -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -methyl benzoate

Prepared by adding n-BuLi to a -78 ° C solution of the compound of Preparation Example 6 (0.39 mmol) and benzylacetylenylstannane (239 mg, 0.59 mmol, benzylacetylene) and then deactivating the activity with tributyltin chloride. Catalytic amounts of PdCl ₂ (Ph ₃ P) ₂ and CuI are added to the THF solution with fresh. The resulting suspension is refluxed for 1 hour. After filtration and evaporation under reduced pressure, the residue is purified using flash chromatography to give the desired product.

Example 13: 4- [6- (3-Phenyl-prop-1-ynyl) -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -benzoic acid
Step 1 : 4- (6-Iodo-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl) -benzoic acid

LiOH (2.25 g, 53.6 mmol) is added to a solution of the compound of Preparation 6 (5.36 mmol) in 10% H ₂ O THF. The reaction is stirred overnight at room temperature. After acidification using concentrated HCl, the reaction mixture is extracted with EtOAc. The organic layer is washed with water and brine, dried (MgSO ₄ ) and filtered under reduced pressure. The crude product is triturated using 4/1 hexane / EtOAc to give the desired compound.

Step 2 : 4- [6- (3-Phenyl-prop-1-ynyl) -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -benzoic acid

To a solution of the compound obtained in step 1 (0.739 mmol) in 6.5 ml of DMF was added diisopropylethylamine (0.381 g, 2.96 mmol), CuI (catalytic amount), 3-phenyl-1-propyne (0 .120 g, 1.03 mmol), and Pd (PPh ₃ ) ₂ Cl ₂ (catalytic amount) are added. The reaction mixture is warmed to 50 ° C. for 4 hours. The mixture is then diluted with 150 ml EtOAc and washed with 3 × 100 ml water, 1 × 100 ml brine. The organic layer is then dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure. The crude product is triturated with 8/1 hexane / EtOAc to give the desired compound.

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

0.2 g (0.671 mmol) of the compound obtained in Preparation Example 7 is dissolved in 50 ml of chloroform. 110 mg 3-methoxybenzylamine, 205 mg Mukaiyama reagent and 163 mg triethylamine are added. The reaction mixture is then stirred overnight at room temperature. The reaction solution is concentrated and purified on a silica gel column with 1: 1 hexane: EtOAc to give 150 mg of the desired compound as a dull white solid.
NMR (CDCl ₃ ) ¹ Hδ (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, 8H), 7.75 (d, J = 8.6Hz, 1H), 8.13 (s, 1H), 8.30 (dd, J ₁ = 8.6Hz, J ₂ = 2.2Hz, 1H), 8.56 (d, J = 2.OHz , 1H).

Example 15: 3- (4-Methanesulfonyl-benzyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide

This compound is obtained according to the procedure described in Example 14 using the compound obtained in Preparation 8 and 4-methoxybenzylamine as reaction substrates.
MS (APCI), M / z 478.1 (M + I).
NMR (DMSO-d ₆ ) ¹ Hδ (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, J = 8.3Hz, 2H), 7.85 (d, J = 8.1Hz, 2H) , 8.16 (d, J = 8.7 Hz, 1H), 8.51 (s, 1H), 9.15 (s, 1H).

Example 16: 4-Oxo-3- [4- (pyrrolidine-1-sulfonyl) -benzyl] -3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide

This compound is obtained according to the procedure described in Example 14 using the compound obtained in Preparation 9 and 4-methoxybenzylamine as reaction substrates.
MS (APCI), M / z 533.2 (M + 1).
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 1.59 (s, 4H), 3.07 (s, 4H), 3.68 (s, 3H), 4.39 (d, J = 5.5Hz, 2H), 5.29 (s, 2H), 6.85 (d, J = 8.3Hz, 2H), 7.23 (d, J = 8.OHz, 2H), 7.25 (s, 1H), 7.54 (d, J = 8.1Hz, 2H), 7.74 (d , J = 8.1 Hz, 2H), 8.26 (d, J = 8.3 Hz, 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

This desired product is obtained by the procedure of Example 14, except that 4-fluorobenzylamine in Step 2 of Preparation 3 is replaced with tert-butyl 3-aminomethylbenzoate and the collected residue is final. Sometimes stirred for 30 minutes in excess trifluoroacetic acid at room temperature. After removing the volatiles under reduced pressure, the residue is filtered to give the desired product as a dull white solid.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.71 (s, 3H), 4.43 (d, J = 4.6Hz, 2H), 5.15 (s, 2H), 6.79 (d, J = 7.6Hz, 1H) , 6.86 (s, 2H), 7.20-7.26 (m, 2H), 7.40 (d, J = 7.3Hz, 2H), 7.86 (d, J = 7.6Hz, 2H), 8.16 (d, J = 8.1Hz, 1H), 8.53 (s, 1H), 9.20 (s, 1H), 11.80 (s, 1H).

Example 18: 4- [4-Oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid
Step 1 : 4- [4-Oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid tert-butyl

3.0 g (6.48 mmol) of the compound of Preparation Example 10 is dissolved in 50 ml of DMF. Then 3.34 g (25.9 mmol) of diisopropylethylamine, catalytic amount of copper (I), 3.01 g (25.9 mmol) of 3-phenyl-1-propyne, and catalytic amount of Pd (PPh ₃ ). ₂ Cl ₂ is added in that order. The reaction solution is stirred for 24 hours at 50 ° C., then diluted with 300 ml EtOAc and washed with 3 × 200 ml water, 1 × 200 ml brine. The organic layer is dried over MgSO ₄ and concentrated. The residue is purified on a silica gel column with hexane: EtOAc gradually increasing from 4: 1 to 1: 1 to give a waxy product as the desired product.
NMR (DMSO-d ₆ ) ¹ Hδ (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 = 8.6Hz, 2H), 8.11 (dd, J ₁ = 8.6Hz, J ₂ = 2.2Hz, 1H), 8.39 (d, J = 2.0Hz, 1H), 8.59 (s, 1H) .

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

An excess (20 ml) of trifluoroacetic acid is added to the compound obtained in step 1 above. After stirring for 30 minutes, all volatiles are distilled off and the residue is triturated with 1: 1 hexane: EtOAc. The precipitate is collected by filtration and washed with a small amount of methanol to give 1.82 g of the desired product as a dull white solid.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.91 (s, 2H), 5.23 (s, 2H), 7.23-7.43 (m, 9H), 7.66 (d, J = 8.3Hz, 1H), 7.83 ( dd, J ₁ = 8.6 Hz, J ₂ = 1.7 Hz, 1H), 7.87 (broad s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 8.58 (s, 1H).

Example 19: 4- {6- [3- (4-Methoxy-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid

This product is obtained by following the procedure of Example 18 with the only difference that the 3-phenyl-1-propyne used in Step 1 is 1-methoxy-4-prop-2-ynyl-benzene. Is replaced by. The product is obtained as a white solid.
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.70 (s, 3H), 3.83 (s, 2H), 5.24 (s, 2H), 6.89 (d, J = 8.5Hz, 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 ₁ = 8.3Hz, J ₂ = 1.5Hz, 1H) 7.88 (d, J = 8.1 Hz, 2H), 8.08 (d, J = 1.5 Hz, 1H), 8.58 (s, 1H), 12.94 (broad s, 1H).

Example 20 4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl-benzamide

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 of DMF. The reaction is stirred for 2 hours under a stream of nitrogen and for an additional 12 hours at room temperature. An excess of 0.5M ammonia in dioxane is then added. The reaction is stirred at room temperature for 1 hour. The solvent is then removed in vacuo and the residue is washed with 1: 1 water: methanol to give 70 mg of a dull white powder as the desired product.
MS (APCI), M / z 394.1 (M + 1).
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 3.92 (s, 2H), 5.21 (s, 2H), 7.24-7.39 (m, 9H), 7.66 (d, J = 8.5Hz, 1H), 7.80- 7.92 (m, 4H), 8.10 (s, 2H), 8.58 (s, 1H).

Example 21: 3- (4-Fluoro-benzyl) -4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl) -amide

The compound of Preparation Example 7 (227 mg, 0.76 mmol), 2-methoxy-pyridin-4-yl-methylamine (138 mg, 1.0 mmol) and Mukaiyama reagent (256 mg, 1.0 mmol) were dissolved in CHCl ₃ (10 ml). Dissolved and Et ₃ N (1 ml, excess) is added. The resulting solution is refluxed for 3 hours and cooled to room temperature. The solution is then purified by flash chromatography to give the desired product as a white solid, 34 mg, 63% yield.
MS (APCI), M / z 419.2 (M + 1).
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 9.40 (t, J = 5.9Hz, 1H), 8.70 (s, 1H), 8.69 (s, 1H), 8.28 (dd, 1H), 8.07 (d, J = 5.4Hz, 1H), 7.77 (d, J = 8.3Hz, 1H), 7.44 (m, 1H), 7.19 (t, J = 8.7Hz, 1H), 6.91 (d, J = 5.1Hz, 1H) , 6.69 (s, 1H), 5.19 (s, 2H), 4.45 (d, J = 5.9Hz, 1H), 3.80 (s, 3H)
Example 22: 3-[(3,5-Difluoro-4-hydroxy) -benzyl] -6- (3-phenyl-prop-1-ynyl) -3H-quinazolin-4-one

3-[(3,5-Difluoro-4-hydroxy) -benzyl] -6-iodo-3H-quinazolin-4-one (obtained according to the procedure of Preparation 3, but in step 2, (3,5-difluoro -4-hydroxy) -benzylamine) (0.3 g, 720 mmol) in 6.5 ml DMF was added to diisopropylethylamine (0.381 g, 2.96 mmol), 3-phenyl-1-propyne. (0.34 g, 2.9 mmol), CuI (catalytic amount), and Pd (PPh ₃ ) ₂ Cl ₂ (catalytic amount) are added. The reaction mixture is heated to 50 ° C. for 4 hours. The mixture is then diluted with 150 ml EtOAc and washed with 3 × 100 ml water, 1 × 100 ml brine. The organic layer is then dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure. The crude product is purified by flash chromatography to give 225 mg of the pure desired product as a pale yellow solid.
MS (APCI), M / z 403.1 (M + 1).
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 8.46 (s, 1H), 8.25 (d, J = 2.0Hz, 1H), 7.1-7.8 (m, 9H), 5.20 (s, 2H), 3.91 ( s, 2H).

Example 23: 3- (3-Fluoro-benzyl) -4-oxo-3,4-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

Starting material 6-chloro-3H-pyrido [3,4-d] pyrimidin-4-one (710 mg, 3.92 mmol, prepared according to J. Chem. Soc., Perkin Trans. 1996, 1, 2221 ) Is dissolved in DMF (20 ml). _{Cs 2 CO 3 (1.66g, 5.1mmol} ) and chloride 3-fluorobenzyl (737 mg, 5.1 mmol) is subsequently added. The reaction is stirred overnight at room temperature and poured into water. After extraction with CH ₂ Cl ₂ , the organic layer is washed with H ₂ O and brine, dried (Na ₂ SO ₄ ) and filtered. After removing the solvent, the residue is purified by flash chromatography to give the product as a white solid.
MS (APCI), M / z 290.0 (M + 1).
NMR (CDCl ₃ ) ¹ Hδ (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 : Methyl 3- (3-fluorobenzyl) -4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylate

The compound obtained in the previous step 1 (3.0 g, 1.07 mmol) is dissolved in 50 ml of methanol together with an excess of triethylamine and a catalytic amount of Pd (dppf) Cl ₂ . The reaction solution is poured into an autoclave and heated at 100 ° C. for 4 hours under a carbon monoxide atmosphere. The reaction is cooled to room temperature and filtered. The filtrate is concentrated in vacuo and the residue is purified on a silica gel column using 1: 1 hexane: EtOAc to give the desired product as a white solid (100%).
MS (APCI), M / z 314.0 (M + 1).
NMR (CDCl ₃ ) ¹ Hδ (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 acid 3-methoxy-benzylamide

To a solution of _3- methoxybenzylamine (144 mg, 1.05 mmol) in CH ₂ Cl ₂ is added AlMe ₃ (0.52 ml, 1.05 mmol). The reaction is stirred at room temperature for 2 hours. A solution of the compound obtained in the previous step 2 (111 mg, 0.35 mmol) in CH ₂ Cl ₂ is then added and the resulting reaction is stirred at room temperature for 2 hours and poured into water. After extraction with CH ₂ Cl ₂ , the organic layer is washed with H ₂ O and brine, dried (Na ₂ SO ₄ ) and filtered. After removing the solvent, the residue is purified by flash chromatography to give the product as a white solid.
MS (APCI), M / z 419.1 (M + 1).
NMR (CDCl ₃ ) ¹ Hδ (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-Fluoro-benzyl) -4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 4-methoxy-benzylamide

This compound is obtained using 4-methoxybenzylamine in its step 3 according to the procedure of Example 23.
MS (APCI), M / z 419.1 (M + 1).
NMR (CDCl ₃ ) ¹ Hδ (ppm): 9.40 (t, 1H), 9.09 (s, 1H), 8.76 (s, 1H), 8.54 (s, 1H), 7.0-7.4 (m, 9H), 6.80 ( d, J = 1.6Hz, 2H), 5.22 (s, 2H), 4.45 (d, J = 6.6Hz, 1H), 3.67 (s, 3H).

Example 25: 4- [4-Oxo-6- (3-phenyl-prop-1,2-dienyl) -4H-quinazolin-3-ylmethyl] -benzoic acid

0.105 g (0.257 mmol) of the compound of Example 9 is dissolved in 25 ml of 90% THF: 10% water. Ten equivalents of LiOH are added. The reaction is refluxed for 3 hours, 200 ml of EtOAc is added, acidified with conc. HCl, and the solution is washed with 2 × 100 ml of water and 1 × 100 ml of brine. The organic layer is dried over MgSO ₄ and concentrated. The residue is purified on a silica gel column with 95% EtOAc: 5% MeOH to give 30 mg of product as a pale yellow powder.
MS (APCI), M / z 481.2 (M + 1).
NMR (DMSO-d ₆ ) ¹ Hδ (ppm): 5.23 (s, 2H), 6.90 (d, J = 6.6Hz, 1H), 7.02 (d, J = 6.6Hz, 1H), 7.24 (m, 1H) , 7.33 (d, J = 4.1,4H), 7.40 (d, J = 8.3Hz, 2H), 7.65 (d, J = 8.3Hz, 1H), 7.75 (dd, J ₁ = 8.5Hz, J ₂ = 1.7 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 8.07 (s, 1H), 8.53 (s, 1H).

Examples 26-71:
These compounds are obtained using the corresponding reaction substrates and reagents according to the procedures described in Preparation Example 5 and Example 8.

26. 4- {6- [3- (4-Methoxy-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
27. 3- (4-Methanesulfonyl-benzyl) -6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
28.4-{(6- [3- (3-Methoxy-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
29. 3- (4-Methanesulfonyl-benzyl) -6- [3- (3-methoxy-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
30.4- [4-oxo-6- (3-pyridin-4-yl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
31.3- (4-Methanesulfonyl-benzyl) -6- (3-pyridin-4-yl-prop-1-ynyl) -3H-quinazolin-4-one,
32.4- [4-Oxo-6- (3-pyridin-3-yl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
33. 3- (4-Methanesulfonyl-benzyl) -6- (3-pyridin-3-yl-prop-1-ynyl) -3H-quinazolin-4-one,
34.4- {6- [3- (4-Fluoro-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
35.6- [3- (4-Fluoro-phenyl) -prop-1-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-quinazolin-4-one,
36.4- {6- [3- (3-Fluoro-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl-benzoic acid,
37.6- [3- (3-Fluoro-phenyl) -prop-1-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-quinazolin-4-one,
38.4- {6- [3- (4-Chloro-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
39.6- [3- (4-Chloro-phenyl) -prop-1-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-quinazolin-4-one,
40.4- {6- [3- (3-chloro-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
41.6- [3- (3-Chloro-phenyl) -prop-1-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-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-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-quinazolin-4-one,
44.4- {6- [3- (3-Bromo-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
45.6- [3- (3-Bromo-phenyl) -prop-1-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-quinazolin-4-one,
46.4- {6- [3- (4-Nitro-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl) -benzoic acid,
47.3- (4-Methanesulfonyl-benzyl) -6- [3- (4-nitro-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
48.4- {6- [3- (2-Methoxy-pyridin-4-yl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
49.3- (4-Methanesulfonyl-benzyl) -6- [3- (2-methoxy-pyridin-4-yl) -prop-1-ynyl] -3H-quinazolin-4-one,
50.4- {6- [3- (4-Methylsulfanyl-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
51.3- (4-Methanesulfonyl-benzyl) -6- [3- (4-methylsulfanyl-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
52.4- {6- [3- (3-Methylsulfanyl-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
53.3- (4-Methanesulfonyl-benzyl) -6- [3- (3-methylsulfanyl-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
54.4- [4-Oxo-6- (3-p-tolyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
55.3- (4-Methanesulfonyl-benzyl) -6- (3-p-tolyl-prop-1-ynyl) -3H-quinazolin-4-one,
56.4- [4-Oxo-6- (3-m-tolyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
57.3- (4-Methanesulfonyl-benzyl) -6- (3-m-tolyl-prop-1-ynyl) -3H-quinazolin-4-one,
58.4- [6- (3-Imidazol-1-yl-prop-1-ynyl) -4-oxo-4H-quinazolin-3-ylmethyl] -benzoic acid,
59.4- [4-Oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzenesulfonamide,
60.4- [4-oxo-6- (3-phenyl-prop-1-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-1-ynyl) -3H-quinazolin-4-one,
63.4- [4-Oxo-6- (3-pyrazol-1-yl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
64.6- (3-Phenyl-prop-1-ynyl) -3- [4- (1H-tetrazol-5-yl) -benzyl] -3H-quinazolin-4-one,
65.3- (3,4-Difluoro-benzyl) -6- [3- (pyridin-4-yloxy) -prop-1-ynyl] -3H-quinazolin-4-one,
66.3- (3,4-difluoro-benzyl) -6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -3H-quinazolin-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-1-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-ylmethyl-3H-quinazolin-4-one.

Examples 72-103:
These compounds are obtained using the corresponding reaction substrates and reagents according to the procedures described in Preparation Example 6 and Example 11.

72,4- {6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl) -benzoic acid,
73. 3- (4-Methanesulfonyl-benzyl) -6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -3H-pyrido [3,4-d] pyrimidin-4-one,
74.4- {6- [3- (3-Methoxy-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl} -benzoic acid,
75.3- (4-Methanesulfonyl-benzyl) -6- [3- (3-methoxy-phenyl) -prop-1-ynyl] -3H-pyrido [3,4-d] pyrimidin-4-one,
76.4- [4-oxo-6- (3-pyridin-4-yl-prop-1-ynyl) -4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -benzoic acid,
77. 3- (4-Methanesulfonyl-benzyl) -6- (3-pyridin-4-yl-prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
78.4- [4-oxo-6- (3-pyridin-3-yl-prop-1-ynyl) -4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -benzoic acid,
79.3- (4-Methanesulfonyl-benzyl) -6- (3-pyridin-3-yl-prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
80.4- {6- [3- (4-Fluoro-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl} -benzoic acid,
81.6- [3- (4-Fluoro-phenyl) -prop-1-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
82.4- {6- [3- (3-Fluoro-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl} -benzoic acid,
83.6- [3- (3-Fluoro-phenyl) -prop-1-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
84.4- {6- [3- (4-Chloro-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl} -benzoic acid,
85.6- [3- (4-Chloro-phenyl) -prop-1-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
86.4- {6- [3- (3-Chloro-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl} -benzoic acid,
87.6- [3- (3-Chloro-phenyl) -prop-1-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
88.4- {6- [3- (4-Bromo-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl} -benzoic acid,
89.6- [3- (4-Bromo-phenyl) -prop-1-ynyl] -3- (4-methanesulfonyl-benzyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
90.4- {6- [3- (3-Bromo-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl} -benzoic acid,
91.6- [3- (3-Bromo-phenyl) -prop-1-ylmethyl] -3- (4-methanesulfonyl-benzyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
92.4- {6- [3- (4-Nitro-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl} -benzoic acid,
93.3- (4-Methanesulfonyl-benzyl) -6- [3- (4-nitro-phenyl) -prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
94.4- {6- [3- (2-Methoxy-pyridin-4-yl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl}- benzoic acid,
95.3- (4-Methanesulfonyl-benzyl) -6- [3- (2-methoxy-pyridin-4-yl) -prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidine-4 -On,
96.4- {6- [3- (4-Methylsulfanyl-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl} -benzoic acid,
97.3- (4-Methanesulfonyl-benzyl) -6- [3- (4-methylsulfanyl-phenyl) -prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
98.4- {6- [3- (3-Methylsulfanyl-phenyl) -prop-1-ynyl] -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl} -benzoic acid,
99.3- (4-Methanesulfonyl-benzyl) -6- [3- (3-methylsulfanyl-phenyl) -prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
100.4- [4-oxo-6- (3-p-tolyl-prop-1-ynyl) -4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -benzoic acid,
101.3- (4-Methanesulfonyl-benzyl) -6- (3-p-tolyl-prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidin-4-one;
102.4- [4-oxo-6- (3-m-tolyl-prop-1-ynyl) -4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -benzoic acid, and 103.3 (4-Methanesulfonyl-benzyl) -6- (3-m-tolyl-prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidin-4-one.

Examples 104 and 105:
These compounds are obtained using the corresponding reaction substrates and reagents according to the procedures described in Examples 14 and 21.

104.3- (3,4-difluoro-benzyl) -4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl) -amide;
105.3- (3,4-Difluoro-benzyl) -4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide.

Pharmacological studies of the compounds of the present invention
Example 106: Evaluation of in vitro activity of MMP-13 inhibitors according to the invention The inhibitory activity of the compound of formula (I) according to the invention on matrix metalloproteinase-13 is determined by proteolysis of the peptide substrate at MMP-13 Is assessed by testing the ability of the compounds of the present invention to inhibit. The peptide substrate used for the test is the following peptide: Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt.

The inhibitory activity of the compound of formula (I) according to the invention is expressed as an IC ₅₀ value which is the concentration of inhibitor at which 50% inhibition of the activity of the matrix metalloproteinase under investigation is observed. To perform this test, it contains 50 mM HEPES buffer, 10 mM CaCl ₂ and 1 mM 5,5′-dithiobis- (2-nitrobenzoic acid) (DTNB), and 100 μM substrate, pH 7. A reaction volume of 100 μl adjusted to 0 is prepared.

  Inhibitor compounds present in the catalytic domain of 2.0% DMSO solution and 2.5 nM human MMP-13 are added to the test sample at increasing concentrations. The concentration of inhibitor present in the test sample ranges from 100 μM to 0.5 nM. The proteolytic measurement of the substrate peptide is followed by measuring the absorbance at 405 nm at the laboratory temperature using a spectrophotometer to read the microplate, and the measurement is performed continuously for 10-15 minutes. .

From the curve in which the percentage of catalytic activity relative to the control is represented on the X-axis and the inhibitor concentration is represented on the Y-axis, IC ₅₀ values are calculated.
The IC ₅₀ values for MMP-13 of the compounds of Examples 1 to 10, 14 to 19, 21, 23 to 25, 58 to 60, 62, 64 to 71, 104, and 105 are all below 1 μM.

Tests described above for inhibition of MMP-13 show that the compound of formula (I) is a matrix metalloproteinase, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, and It was also adapted and used to measure the ability to inhibit MMP-14. The results obtained, the compounds according to the present invention, generally, the MMP-13, to have about 100 times lower an IC ₅₀ value than an IC ₅₀ value for the same compounds for other matrix metal protease tested It is shown.

Claims (33)

A compound of the formula (I):

{In the formula:
X ₁ , X ₂ , and X ₃ each independently represent a nitrogen atom or a group —CR ₃ , where R ₃ is hydrogen, (C ₁ -C ₆ ) alkyl, amino, mono (C ₁ -C ₆₎ represents alkylamino, di (C ₁ ~C ₆₎ alkylamino, hydroxy, a group selected (C ₁ ~C ₆₎ alkoxy, and halogen, with the proviso that the groups X _1, X _2, and X 2 or less of ₃ simultaneously represents a nitrogen atom;
G ₁ is the formula (i / a) and (i / b):

[Where:
The carbon atom having the number 2 is bonded to the group N—R ₁ in the ring;
R ₄ and R ₅ may be the same or different and are independently of each other hydrogen, (C ₁ -C ₆ ) alkyl, aryl, aryl (C ₁ -C ₆ ) alkyl, cycloalkyl, cycloalkyl (C _1- C ₆ ) represents a group selected from alkyl, heteroaryl, heteroaryl (C ₁ -C ₆ ) alkyl, heterocycloalkyl, and heterocycloalkyl (C ₁ -C ₆ ) alkyl;
R ₆ is
Hydrogen, trifluoromethyl, OR ₇ , NR ₇ R ₈ (R ₇ and R ₈ may be the same or different and each independently represents hydrogen or (C ₁ -C ₆ ) alkyl),
(C ₁ ~C ₆₎ alkyl, (C ₂ ~C ₆₎ alkenyl, (C ₂ ~C ₆₎ alkynyl, aryl, aryl (C ₁ ~C ₆₎ alkyl, cycloalkyl (C ₁ ~C ₆₎ alkyl, Heteroaryl, heteroaryl (C ₁ -C ₆ ) alkyl, heterocycloalkyl, and heterocycloalkyl (C ₁ -C ₆ ) alkyl, including halogen, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino (each alkyl moiety may be the same or different and are independent of each other), cyano, trihalogeno (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acyl,- One or more selected from C (═O) OR ₇ , —OR ₇ and —SR ₇ (where R ₇ is as defined above), which may be the same or different, and are substituted by groups independent of each other. Even if It represents a group selected from the casting. ]
A group selected from:
G ₂ is a carbon-carbon triple bond, —CH═C═CH—, C═O, C═S, S (O) _n1 (n1 represents an integer of 0 to 2), and a formula (i / c ):

[Where:
The carbon atom having the number 1 is attached to the bicyclic ring of the compound of formula (I) and Y ₁ is selected from oxygen, sulfur, —NH and —N (C ₁ -C ₆ ) alkyl. And Y ₂ represents a group selected from oxygen, sulfur, —NH, and —N (C ₁ -C ₆ ) alkyl. ]
Represents a group selected from:
-N represents an integer of 0-6;
Z ₁ represents —CR ₉ R ₁₀ , and R ₉ and R ₁₀ may be the same or different, and independently of each other, hydrogen, (C ₁ -C ₆ ) alkyl, trihalogeno (C ₁ -C ₆ ) Alkyl, halogen, —OR ₇ , —SR ₇ , —C (═O) OR ₇ (R ₇ is as defined above), amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆₎ alkylamino (the alkyl moiety thereof represents a group selected from a well independently be the same or different), and when n is equal to greater than or 2, the hydrocarbon chain Z ₁ is Can contain 1 to 2 isolated or conjugated multiple bonds, and / or
When n is greater than or equal to 2, one of the —CR ₉ R ₁₀ is oxygen, S (O) _n1 (where n1 is as defined above), —NH and —N (C _1- C ₆ ) may be substituted with a group selected from alkyl;
A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, and these rings are 5-membered or 6-membered monocycles or are composed of two 5-membered or 6-membered monocycles A bicyclic ring;
・ R ₁ is
hydrogen,
(C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, amino, cyano, trihalogeno (C ₁ -C ₆ ) alkyl, cycloalkyl, —C ( ═O) NR ₇ R ₈ , —C (═O) OR ₈ , —OR ₈ , —SR ₈ (R ₇ and R ₈ may be the same or different and independently of each other hydrogen or (C ₁ -C ₆ ) representing alkyl) one or more selected from the same or different, optionally substituted with groups independent of each other, and
Formula (i / d):

[Where:
p is an integer of 0 to 8,
Z ₂ represents —CR ₁₁ R ₁₂ , and R ₁₁ and R ₁₂ may be the same or different, and independently of each other, hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, trihalogeno (C ₁ -C ₆ ) Represents a group selected from alkyl, halogen, amino, —OR ₇ , —SR ₇ and —C (═O) OR _{7, where} R ₇ represents hydrogen or (C ₁ -C ₆ ) alkyl, and p Is greater than or equal to ₂ , the hydrocarbon chain Z ₂ can contain 1 or 2 isolated or conjugated multiple bonds, and / or
When n is greater than or equal to 2, one of the —CR ₁₁ R ₁₂ is oxygen, S (O) _n1 (n1 is as defined above), —NH, —N (C _1- C ₆ ) may be substituted with a group selected from alkyl and carbonyl,
B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, which are 5-membered or 6-membered monocycles or composed of two 5-membered or 6-membered monocycles Bicyclic,
q is an integer of 0 to 7,
The groups G ₃ may be the same or different and, independently of one another, (C ₁ -C ₆ ) alkyl, halogen, CN, NO ₂ , CF ₃ , OCF ₃ , — (CH ₂ ) _k NR ₁₃ R ₁₄ , — _{N (R 13) C (=} O) R 14, -N (R 13) C (= O) OR 14, -N (R 13) SO 2 R 14, -N (SO 2 R 13) 2, -OR ₁₃ , —S (O) _k1 R ₁₃ , —SO ₂ —N (R ₁₃ ) — (CH ₂ ) _{k 2} —NR ₁₄ R ₁₅ , — (CH ₂ ) _k SO ₂ NR ₁₃ R ₁₄ , —X ₄ (CH _{2) k C (= O)} OR 13, - (CH 2) k C (= O) OR 13, -C (= O) O- (CH 2) k2 -NR 13 R 14, -C (= O) O— (CH ₂ ) _k2 —C (═O) OR ₁₆ , —X ₄ (CH ₂ ) _k C (═O) NR ₁₃ R ₁₄ , — (CH ₂ ) _k C (═O) NR ₁₃ R ₁₄ , Selected from —R ₁₇ —C (═O) OR ₁₃ , —X ₅ —R ₁₈ , and —C (═O) —R ₁₉ —NR ₁₃ R ₁₄ , where:
X ₄ represents a group selected from an oxygen atom, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group,
k is an integer of 0 to 3,
k1 is an integer of 0 to 2,
k2 is an integer of 1 to 4,
R ₁₃ , R ₁₄ and R ₁₅ may be the same or different and are independently of each other selected from hydrogen and (C ₁ -C ₆ ) alkyl;
R ₁₆ is (C ₁ -C ₆ ) alkyl, —R ₁₉ —NR ₁₃ R ₁₄ , —R ₁₉ —NR ₁₃ —C (═O) —R ₁₉ —NR ₁₄ R ₁₅ , and —C (═O) From O—R ₁₉ —NR ₁₃ R ₁₄ (R ₁₉ represents a linear or branched (C ₁ -C ₆ ) alkylene group, and R ₁₃ , R ₁₄ and R ₁₅ are as defined above). Represents the selected group,
R ₁₇ represents a (C ₃ -C ₆ ) cycloalkyl group,
X ₅ represents a single bond, —CH ₂ —, an oxygen atom, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group. Represents a group selected from
R ₁₈ is
5- or 6-membered monocyclic aryl, heteroaryl, (C ₁ -C ₆ ) alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and —C (═O) OR ₇ (R ₇ is hydrogen or ( C ₁ -C ₆ ) representing alkyl) one or more selected from the same or different, optionally substituted by independent groups, and 5- or 6-membered monocyclic cycloalkyl, Heterocycloalkyl, (C ₁ -C ₆ ) alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and —C (═O) OR ₇ (R ₇ is hydrogen or (C ₁ -C ₆ ) Represents a group selected from those optionally substituted by one or more groups which may be the same or different, selected from alkyl. ]
Represents a group selected from:
M is an integer from 0 to 7;
The radicals R ₂ may be the same or different and, independently of one another, (C ₁ -C ₆ ) alkyl, halogen, —CN, NO ₂ , SCF ₃ , —CF ₃ , OCF ₃ , —NR ₇ R ₈ , _{-OR 8, -SR 8, -SOR 8} , -SO 2 R 8, - (CH 2) k SO 2 NR 7 R 8, -X 7 (CH 2) k C (= O) OR 8, - (CH _{2) k C (= O)} oR 8, -X 7 (CH 2) k C (= O) NR 7 R 8, - (CH 2) k C (= O) NR 7 R 8, and -X ₈ - Selected from R ₂₀ where:
X ₇ represents a group selected from oxygen, sulfur optionally substituted by 1 or 2 oxygen atoms, and hydrogen or nitrogen substituted by a (C ₁ -C ₆ ) alkyl group;
k is an integer of 0 to 3,
R ₇ and R ₈ may be the same or different and are independently of each other selected from hydrogen and (C ₁ -C ₆ ) alkyl;
X ₈ is a single bond, —CH ₂ —, an oxygen atom, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group Represents a group selected from
R ₂₀ is 5-membered or 6-membered monocyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, which is 1 or selected from (C ₁ -C ₆ ) alkyl, halogen, hydroxy, and amino Optionally substituted by an identical or different group, and when the ring is a heterocycle, it comprises 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur . }
A compound selected from those described above, its racemate, its isomer, its N-oxide, and pharmaceutically acceptable salts thereof, unless otherwise specified,
An aryl group represents an aromatic monocyclic or bicyclic ring system containing 5 to 10 carbon atoms, in which case one ring is aromatic and the other ring is aromatic. But it may be partially hydrogenated,
A heteroaryl group represents the above aryl group wherein 1 to 4 carbon atoms are replaced by 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;
A cycloalkyl group represents a monocyclic or bicyclic system containing from 3 to 10 carbon atoms, which system is partially unsaturated without saturation or aromaticity, and a heterocycloalkyl group is As defined above, it represents a cycloalkyl group in which 1-4 carbon atoms are replaced by 1-4 heteroatoms selected from oxygen, sulfur and nitrogen. A compound of claim 1 comprising:
G ₂ is C═O, _C═S , S (O) _n1 (n1 represents an integer of 0 to 2), or formula (i / c):

[Where:
The carbon atom having the number 1 is attached to the bicyclic ring of the compound of formula (I) and Y ₁ is selected from oxygen, sulfur, —NH and —N (C ₁ -C ₆ ) alkyl. And Y ₂ represents a group selected from oxygen, sulfur, —NH and —N (C ₁ -C ₆ ) alkyl. ]
Represents a group selected from:
X ₁ , X ₂ , X ₃ , G ₁ , n, Z ₁ , A, R ₁ , m and R ₂ are as defined in formula (I),
The compound, its racemate, its isomer, its N-oxide, and pharmaceutically acceptable salts thereof. A compound of claim 1 comprising:
G ₂ represents a carbon-carbon triple bond;
n represents an integer of 1 to 6;
X ₁ , X ₂ , X ₃ , G ₁ , Z ₁ , A, R ₁ , m and R ₂ are as defined in formula (I),
The compound, its racemate, its isomer, its N-oxide, and pharmaceutically acceptable salts thereof. A compound of claim 1 comprising:
G ₂ represents a carbon-carbon triple bond;
n is 0;
Z ₁ is not present;
A represents a group selected from heteroaryl, cycloalkyl, and heterocycloalkyl, and these rings are 5-membered or 6-membered monocycles, or bicycles composed of two 5-membered or 6-membered monocycles Is;
X ₁ , X ₂ , X ₃ , G ₁ , R ₁ , m and R ₂ are as defined in formula (I),
The compound, its racemate, its isomer, its N-oxide, and pharmaceutically acceptable salts thereof. A compound of claim 1 comprising:
G ₂ represents a carbon-carbon triple bond;
n is 0;
Z ₁ is not present;
A represents a phenyl group;
R ₁ is a hydrogen atom, or formula (i / d):

[Where:
p is an integer of 0 to 8,
Z ₂ represents —CR ₁₁ R ₁₂ , and R ₁₁ and R ₁₂ may be the same or different, and independently of each other, hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, trihalogeno (C ₁ -C ₆ ) Represents a group selected from alkyl, halogen, amino, —OR ₇ , —SR ₇ and —C (═O) OR _{7, where} R ₇ represents hydrogen or (C ₁ -C ₆ ) alkyl, and p Is greater than or equal to ₂ , the hydrocarbon chain Z ₂ can contain 1 or 2 isolated or conjugated multiple bonds, and / or
When n is greater than or equal to 2, one of the —CR ₁₁ R ₁₂ is oxygen, S (O) _n1 (n1 is as defined above), —NH, —N (C _1- C ₆ ) may be substituted with a group selected from alkyl and carbonyl,
B represents a phenyl group;
q is an integer of 1 to 7,
The groups G ₃ may be the same or different and independently of each other —— (CH ₂ ) _k NR ₁₃ R ₁₄ , —N (R ₁₃ ) C (═O) OR ₁₄ , —N (R ₁₃ ) SO ₂ R ₁₄ , —N (SO ₂ R ₁₃ ) ₂ , —S (O) _k1 R ₁₃ , —SO ₂ —N (R ₁₃ ) — (CH ₂ ) _{k 2} —NR ₁₄ R ₁₅ , — (CH ₂ ) _k SO ₂ NR ₁₃ R ₁₄ , —X ₄ (CH ₂ ) _k C (═O) OR ₁₃ , — (CH ₂ ) _k C (═O) OR ₁₃ , —C (═O) O— (CH ₂ ) _{k 2} —NR ₁₃ R ₁₄ , —C (═O) O— (CH ₂ ) _{k 2} —C (═O) OR ₁₆ , —X ₄ (CH ₂ ) _k C (═O) NR ₁₃ R ₁₄ , — (CH ₂ ) _k C (═O) NR ₁₃ R ₁₄ , —R ₁₇ —C (═O) OR ₁₃ , —X ₅ —R ₁₈ , —C (═O) —R ₁₉ —NR ₁₃ R ₁₄ and —X ₆ —R ₂₁ Where is selected from:
X ₄ represents a group selected from an oxygen atom, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group,
k is an integer of 0 to 3,
k1 is an integer of 1 to 2,
k2 is an integer of 1 to 4,
R ₁₃ , R ₁₄ and R ₁₅ may be the same or different and are independently of each other selected from hydrogen and (C ₁ -C ₆ ) alkyl;
R ₁₆ is (C ₁ -C ₆ ) alkyl, —R ₁₉ —NR ₁₃ R ₁₄ , —R ₁₉ —NR ₁₃ —C (═O) —R ₁₉ —NR ₁₄ R ₁₅ , and —C (═O) From O—R ₁₉ —NR ₁₃ R ₁₄ (R ₁₉ represents a linear or branched (C ₁ -C ₆ ) alkylene group, and R ₁₃ , R ₁₄ and R ₁₅ are as defined above). Represents the selected group,
R ₁₇ represents a (C ₃ -C ₆ ) cycloalkyl group,
X ₅ represents a single bond, —CH ₂ —, an oxygen atom, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group. Represents a group selected from
R ₁₈ represents heteroaryl, cycloalkyl, heterocycloalkyl, these groups are 5-membered or 6-membered monocycles or bicyclics composed of two 5-membered or 6-membered monocycles, (C ₁ -C ₆₎ alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and _{-C (= O) oR 7 (} R 7 is hydrogen or (C ₁ -C ₆₎ alkyl) is selected from One or more of the same or different, which may be substituted by groups independent of each other,
X ₆ represents a group selected from —CH ₂ —, a sulfur atom optionally substituted by 1 or 2 oxygen atoms, and a nitrogen atom substituted by a hydrogen atom or a (C ₁ -C ₆ ) alkyl group. Represent,
R ₂₁ is a phenyl group and is (C ₁ -C ₆ ) alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and —C (═O) OR ₇ (R ₇ is hydrogen or (C ₁ -C _6). ) Represents an alkyl group) and may be substituted by one or more of the same or different groups and independent of each other. ]
Represents a group of
X ₁ , X ₂ , X ₃ , G ₁ , m and R ₂ are as defined in formula (I),
The compound, its racemate, its isomer, its N-oxide, and pharmaceutically acceptable salts thereof. A compound of claim 1 comprising:
R ₁ represents the formula (i / d):

(Wherein Z ₂ , p, B, G ₃ , and q are as defined for the compound of formula (I).)
The compound, its racemate, its isomer, its N-oxide, and pharmaceutically acceptable salts thereof. A compound of claim 6, Z ₂ represents a group -CR ₁₁ R _12, R ₁₁ and R ₁₂ represents a hydrogen atom, the compound, its racemate, its isomers, its N- oxides and pharmaceutical, Acceptable salt.   7. The compound of claim 6, wherein p is 1, its racemate, its isomer, its N-oxide, and pharmaceutically acceptable salts thereof. A compound of claim 6, B represents a phenyl group, q is equal to 0 or 1, is G _3, when present, -OR _13, halogen, -S (O) _k1 R ₁₃ and, — (CH ₂ ) _k C (═O) OR ₁₃ (R ₁₃ represents a hydrogen atom or a (C ₁ -C ₆ ) alkyl group), k is 0, and k1 is 2 A compound, a racemate thereof, an isomer thereof, an N-oxide thereof, and a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein G ₁ represents a group of formula (i / a), wherein R ₄ represents a hydrogen atom or a methyl group, or G ₁ represents a group of formula (i / b). Wherein R ₄ and R ₅ are the same and each represents a hydrogen atom or a methyl group, and R ₆ represents a hydrogen atom or a methyl group, a racemate, an isomer thereof, an N-oxide thereof, And pharmaceutically acceptable salts thereof. The compound of claim 1, wherein X ₁ represents a group -CR ₃ , wherein R ₃ represents a hydrogen atom, X ₂ represents a nitrogen atom or a group -CR ₃ , wherein R ₃ represents hydrogen. A compound, its racemate, its isomer, its N-oxide, and its pharmaceutically acceptable salt, which represents an atom and X ₃ represents a group —CR ₃ , wherein R ₃ represents a hydrogen atom . The compound of claim 1, wherein G ₂ represents a carbon-carbon triple bond or a group of formula (i / c), wherein Y ₁ represents an oxygen atom and Y ₂ represents a group -NH. , Its racemates, its isomers, its N-oxides, and pharmaceutically acceptable salts thereof. The compound of claim 1, wherein Z ₁ represents -CR ₉ R ₁₀ , wherein R ₉ and R ₁₀ each represent hydrogen and n is 1, the racemate, its isomer, N-oxides and pharmaceutically acceptable salts thereof. The compound of claim 1, wherein A represents a group selected from phenyl or pyridyl, m is equal to 0 or 1, and R ₂ represents a (C ₁ -C ₆ ) alkoxy group or a hydrogen atom. , Its racemates, its isomers, its N-oxides, and pharmaceutically acceptable salts thereof. 2. The compound of claim 1 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-methoxy-benzylamide, hydrochloride,
3- (4-methoxy-benzyl) -1-methyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 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-1,4-dihydro-2H-quinazolin-3-ylmethyl] -benzoic acid,
4- [6- (4-methoxy-benzylcarbamoyl) -1-methyl-4-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl] -benzoic acid methyl ester,
4- [6- (4-methoxy-benzylcarbamoyl) -1-methyl-4-oxo-1,4-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,
4-oxo-3- [4- (pyrrolidine-1-sulfonyl) -benzyl] -3,4-dihydro-quinazoline-6-carboxylic acid 4-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] 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- Dihydro-benzyl) -4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide. 2. The compound of claim 1 selected from:
3- (4-fluorobenzyl) -6- (3-phenyl-prop-1-ynyl) -3H-quinazolin-4-one,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -methyl benzoate,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
3- (4-fluorobenzyl) -6- (3-phenyl-prop-1-ynyl) -3H-pyrido [3,4-d] pyrimidin-4-one,
4- [6- (3-phenyl-prop-1-ynyl) -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -methyl benzoate;
4- [6- (3-phenyl-prop-1-ynyl) -4-oxo-4H-pyrido [3,4-d] pyrimidin-3-ylmethyl] -benzoic acid,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
4- {6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzamide,
3-[(3,5-difluoro-4-hydroxy) -benzyl] -6- (3-phenyl-prop-1-ynyl) -3H-quinazolin-4-one,
4- [6- (3-imidazol-1-yl-prop-1-ynyl) -4-oxo-4H-quinazolin-3-ylmethyl] -benzoic acid,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzenesulfonamide,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzonitrile,
3- (3-chloro-benzyl) -6- (4-phenyl-but-1-ynyl) -3H-quinazolin-4-one,
3- (3-chloro-benzyl) -6- (3-phenyl-but-1-ynyl) -3H-quinazolin-4-one,
4- [4-oxo-6- (3-pyrazol-1-yl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzoic acid,
6- (3-phenyl-prop-1-ynyl) -3- [4- (1H-tetrazol-5-yl) -benzyl] -3H-quinazolin-4-one,
3- (3,4-dihydro-benzyl) -6- [3- (pyridin-4-yloxy) -prop-1-ynyl] -3H-quinazolin-4-one,
3- (3,4-dihydro-benzyl) -6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
N- {4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -phenyl} -acetamide,
3- (3,4-difluoro-benzyl) -6- (3-phenyl-prop-1-ynyl) -3H-quinazolin-4-one,
3- (4-acetyl-benzyl) -6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
6- (3-Phenyl-prop-1-ynyl) -3-pyridin-4-ylmethyl-3H-quinazolin-4-one, and 6- [3- (4-Methoxy-phenyl) -prop-1-ynyl] -3-Pyridin-4-ylmethyl-3H-quinazolin-4-one. 2. The compound of claim 1 selected from:
Methyl 4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] benzoate,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] benzoic acid,
4- [6- (3-methoxy-benzylcarbamoyl) -4-oxo-4H-quinazolin-3-ylmethyl] benzoic acid,
4- {6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -4-oxo-4H-quinazolin-3-ylmethyl} -benzoic acid,
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,
4- [6- (3-imidazol-1-yl-prop-1-ynyl) -4-oxo-4H-quinazolin-3-ylmethyl] -benzoic acid,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzenesulfonamide,
4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -benzonitrile,
6- (3-phenyl-prop-1-ynyl) -3- [4- (1H-tetrazol-5-yl) -benzyl] -3H-quinazolin-4-one,
3- (3,4-difluoro-benzyl) -6- [3- (pyridin-4-yloxy) -prop-1-ynyl] -3H-quinazolin-4-one,
3- (3,4-difluoro-benzyl) -6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
N- {4- [4-oxo-6- (3-phenyl-prop-1-ynyl) -4H-quinazolin-3-ylmethyl] -phenyl} -acetamide,
3- (4-acetyl-benzyl) -6- [3- (4-methoxy-phenyl) -prop-1-ynyl] -3H-quinazolin-4-one,
6- (3-Phenyl-prop-1-ynyl) -3-pyridin-4-ylmethyl-3H-quinazolin-4-one, and 6- [3- (4-Methoxy-phenyl) -prop-1-ynyl] -3-Pyridin-4-ylmethyl-3H-quinazolin-4-one. A method for producing the compound of claim 1, comprising:
Formula (II):

Wherein X ₁ , X ₂ , X ₃ and Y ₁ have the same definition as the compound of formula (I) of claim 1 and T represents a (C ₁ -C ₆ ) alkyl group. Represent. ]
Is used as a starting material,
The compound of formula (II) is represented by formula (III):

[Wherein Z ₁ , Y ₂ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
And the acid function in the presence of diisopropylethylamine and a solvent by activating with an activating agent to give a compound of formula (IV):

[Wherein, X ₁ , X ₂ , X ₃ , Y ₁ , T, Z ₁ , Y ₂ , R ₂ , A, n and m are as defined above]. ]
Produces a compound of
Then, a compound the ester group of the compound was obtained after being hydrolyzed formula (IV) is a base, the general formula R ₁ -NH ₂ R ₁ is defined as in the compounds of formula (I) Treated with an activator in the presence of a primary amine to give a compound of formula (V):

[Wherein, X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Z ₁ , R ₂ , R ₁ , A, n and m are as defined above]. ]
Produces a compound of
The compound of formula (V) is
Formula (I / a), which is a special case of a compound of formula (I), treated under heating conditions with triethyl orthoformate:

[Wherein, X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Z ₁ , R ₂ , R ₁ , A, n and m are as defined above]. ]
Or a compound of
Under heating conditions in the presence of acid, formula (VI):

[Wherein R ₄ has the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) treated with a compound of formula (I / b):

[Wherein, X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Z ₁ , R ₂ , R ₁ , R ₄ , A, n and m are as defined above]. ]
Or a compound of
Under basic conditions, formula (VII):

[Wherein R ₄ and R ₅ have the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) treated with a compound of formula (I / c):

[Wherein, X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Z ₁ , R ₂ , R ₁ , R ₄ , R ₅ , A, n and m are as defined above]. ]
Produces a compound of
Optionally, the compound of formula (I / c) is a hydride and a compound of formula (VIII):

[Wherein R ₆ has the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I), treated in the presence of a compound of formula (I / d):

[Wherein X ₁ , X ₂ , X ₃ , Y ₁ , Y ₂ , Z ₁ , R ₂ , R ₁ , R ₄ , R ₅ , R ₆ , A, n and m are as defined above] is there. ]
A method of producing a compound of
Compounds of formula (I / a), (I / b), (I / c) and (I / d) constitute several compounds of the present invention, which, if appropriate, are conventional Purified according to conventional purification techniques, if appropriate separated into their different isomers according to conventional separation techniques, and where appropriate to their addition salts with pharmaceutically acceptable acids or bases. Or a process to convert them to their N-oxides. A method for producing the compound of claim 1, comprising:
Formula (X):

[Wherein X ₁ , X ₂ , and X ₃ have the same definition as the compound of formula (I) of claim 1, and Hal represents a halogen atom. ]
Is used as a starting material,
A compound of formula (X) is treated with a derivative of phosgene in a first step to give a compound of formula (XI):

[Wherein X ₁ , X ₂ , X ₃ and Hal are as defined above. ]
Produces a compound of
Compound of formula (XI), with a base medium, R ₁ to have been treated with a primary amine of general formula R ₁ -NH ₂ having the same definition as the compound of Formula (I), Formula (XII):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and Hal are as defined above. ]
Produces a compound of
The compound of formula (XII) is
Treated with triethyl orthoformate under heating conditions to give the formula (XIII / a):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and Hal are as defined above. ]
Or a compound of
Under heating conditions in the presence of acid, formula (VI):

[Wherein R ₄ has the same definition as the compound of formula (I). ]
Treated with a compound of formula (XIII / b):

[Wherein, X ₁ , X ₂ , X ₃ , Hal, R ₁ and R ₄ are as defined above. ]
Or a compound of
Under basic conditions, formula (VII):

[Wherein R ₄ and R ₅ have the same definition as the compound of formula (I). ]
Treated with a compound of formula (XIII / c):

[Wherein, X ₁ , X ₂ , X ₃ , Hal, R ₁ , R ₄ , and R ₅ are as defined above. ]
Produces a compound of
Optionally, the compound of formula (XIII / c) is a hydride and a compound of formula (VIII):

[Wherein R ₆ has the same definition as the compound of formula (I), and Hal is a halogen atom. ]
A specific case of a compound of formula (I), treated in the presence of a compound of formula (XIII / d):

[Wherein, X ₁ , X ₂ , X ₃ , Hal, R ₁ , R ₄ , R ₅ and R ₆ are as defined above. ]
Produces a compound of
All compounds of formula (XIII / a), (XIII / b), (XIII / c) and (XIII / d) are represented by formula (XIII / e):

[Wherein X ₁ , X ₂ , X ₃ , Hal, R ₁ and G ₁ are as defined in the compound of formula (I). ]
Composed of
A compound of formula (XIII / e) is prepared under the conditions of palladium catalyzed alkynylation:

[Wherein Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) treated with a compound of formula (I / e):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ , G ₁ , Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
A method of producing a compound of
Compounds of formula (I / e) constitute several compounds of the invention, which are purified according to conventional purification techniques, where appropriate, and where appropriate, conventional separation techniques. According to the invention, and where appropriate converted to their addition salts or to their N-oxides with pharmaceutically acceptable acids or bases. A method for producing the compound of claim 1, comprising:
Formula (XIII / e):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and G ₁ are as defined in the compound of formula (I), and Hal is a halogen atom. ]
Is used as a starting material,
A compound of formula (XIII / e) is prepared in the presence of dichlorobis (triphenylphosphine) palladium, copper iodide, and N, N′-diisopropylethylamine in dimethylformamide:

[Wherein Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) condensed with a compound of formula (I / e):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ , G ₁ , Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
To produce a compound of A method for producing the compound of claim 1, comprising:
Formula (XIII / e):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and G ₁ are as defined in the compound of formula (I), and Hal is a halogen atom. ]
Is used as a starting material,
A compound of formula (XIII / e) is reacted with carbon monoxide in an alkaline medium in the presence of a protic solvent and a catalytic amount of palladium to produce a compound of formula (XVI):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and G ₁ are as defined in the compound of formula (I). ]
Produces a compound of
A compound of formula (XVI) is hydrolyzed in a basic medium to give formula (XVII):

[Wherein X ₁ , X ₂ , X ₃ , R ₁ and G ₁ are as defined in the compound of formula (I). ]
Produces a compound of
A compound of formula (XVII) is synthesized in the presence of Mukayama reagent in a basic medium, formula (XVIII):

[Wherein Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) condensed with a compound of formula (I / f):

[Wherein X ₁ , X ₂ , X ₃ , Z ₁ , R ₂ , R ₁ , A, n and m are as defined above]. ]
A method of producing a compound of
Compounds of formula (I / f) constitute several compounds of the invention, which are purified according to conventional purification techniques, where appropriate, and where appropriate, conventional separation techniques. According to the invention, and where appropriate converted to their addition salts or to their N-oxides with pharmaceutically acceptable acids or bases. A method for producing the compound of claim 1, comprising:
Formula (XIX):

[Wherein Hal represents a halogen atom. ]
Is used as a starting material,
A compound of formula (XIX) is heated in the presence of formamidine acetate in a polar solvent to yield formula (XX):

[Wherein Hal is as defined above. ]
Produces a compound of
A compound of formula (XX) is treated with a compound of formula R ₁ -Hal in a basic medium, wherein R ₁ is as defined in the compound of formula (I) and Hal represents a halogen atom, to give a compound of formula (XXI ):

[Wherein Hal and R ₁ are as defined above. ]
Produces a compound of
A compound of formula (XXI) is reacted with carbon monoxide in a basic medium in the presence of an alcohol solvent and a catalytic amount of palladium to produce a compound of formula (XXII):

[Wherein R ₁ is as defined above. ]
Produces a compound of
A compound of formula (XXII) is prepared in the presence of trimethylaluminum in formula (XVIII):

[Wherein Z ₁ , R ₂ , A, n and m have the same definition as the compound of formula (I). ]
A specific case of a compound of formula (I) condensed with a compound of formula (I / g):

[Wherein Z ₁ , R ₂ , R ₁ , A, n and m are as defined above. ]
A method of producing a compound of
The compounds of formula (I / g) constitute several compounds of the invention, which are purified according to conventional purification techniques, where appropriate, and where appropriate, conventional separation techniques. According to the invention, and where appropriate converted to their addition salts or to their N-oxides with pharmaceutically acceptable acids or bases.   A method of treating a living body suffering from a disease involving inhibition of type 13 matrix metalloproteinase, comprising the step of administering to the living body an amount of the compound of claim 1 effective to alleviate the condition. A method comprising.   Arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, inflammatory bowel disease, psoriasis, multiple sclerosis, heart failure, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration, and A method of treating a living body suffering from a disease selected from cancer, comprising the step of administering to the living body an amount of the compound of claim 1 effective to alleviate the condition.   A pharmaceutical composition comprising an effective amount of the compound of claim 1 as an active ingredient alone or in combination with one or more pharmaceutically acceptable excipients or carriers.   24. A pharmaceutical composition useful in the method of claim 23 comprising an effective amount of the compound of claim 1 as an active ingredient together with one or more pharmaceutically acceptable excipients or carriers.   24. A pharmaceutical composition useful in the method of claim 23, comprising an effective amount of the compound of claim 16 as an active ingredient together with one or more pharmaceutically acceptable excipients or carriers.   24. A pharmaceutical composition useful in the method of claim 23, comprising an effective amount of the compound of claim 17 as an active ingredient together with one or more pharmaceutically acceptable excipients or carriers.   Use of a compound according to claim 1 for the manufacture of a medical product for the treatment of diseases including therapy by inhibition of type 13 matrix metalloproteinases.   The disease is arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, inflammatory bowel disease, psoriasis, multiple sclerosis, heart failure, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related 30. Use according to claim 29, which is macular degeneration and cancer.   31. Use according to claim 30, wherein the disease is arthritis.   31. Use according to claim 30, wherein the disease is osteoarthritis.   31. Use according to claim 30, wherein the disease is rheumatoid arthritis.