CN1738806A - Oxo-azabicyclic compounds - Google Patents
Oxo-azabicyclic compounds Download PDFInfo
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- CN1738806A CN1738806A CNA038048752A CN03804875A CN1738806A CN 1738806 A CN1738806 A CN 1738806A CN A038048752 A CNA038048752 A CN A038048752A CN 03804875 A CN03804875 A CN 03804875A CN 1738806 A CN1738806 A CN 1738806A
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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Abstract
A compound selected from those of formula (I) wherein: X1, X2, and X3, represent N or -CR3 in which R3 is as described in the description, G1 represents a group selected from those of formulae (i/a) and (i/b) in which R4, R5, and R6 are as defined in the description, G2 represents a group selected from carbon-carbon triple bond, -CH=C=CH-, C=O, C=S, S(O)n1 in which n1 represents an integer from 0 to 2 inclusive, or a group of formula (i/c) in which Y1 represents O, S, -NH or -Nalkyl, and Y2 represents O, S, -NH or -Nalkyl, n is an integer from 0 to 6 inclusive, and m is an integer from 0 to 7 inclusive, Z1 represents -CR9R10,wherein R9 and R10 are as defined in the description, A represents a ring system, R1 represents a group selected from H, alkyl, alkenyl, alkynyl, optionally substituted and the group of formula (i/d) in which P, Z2, B, q and G3 are as defined in the description and optionally, its optical isomers, N-oxide, and addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same are useful as specific inhibitors of type-13 matrix mettaloprotease.
Description
Technical field
The present invention relates to novel oxo Azabicyclic compounds, it can be used for _ prepare the pharmaceutical prod for the use of treatment disease symptoms, and described treatment relates to use matrix metalloproteinase-13 (MMP-13) agent and treats.These pharmaceutical prods especially can be used for treating specific inflammatory diseases, such as rheumatic arthritis or osteoarthritis and specific proliferative disease such as cancer.
Prior art
(matrix metalloproteases is MMPs) for participating in the enzyme of extracellular matrix tissue such as the renewal in cartilage, tendon and joint for matrix metalloproteinase.MMP causes the destruction of extracellular matrix, under non-pathologic physiological status, compensates by regeneration simultaneously.
Under the normal physiological state, (control by the tissue depressant (TIMPs) such as metalloprotease by the specific protein that suppresses MMP for these activity that have an aggressive peptase.
The active partial balancing of MMPs and TIPMs is to the extremely important property of the renewal of extracellular matrix.The equilibrated change causes MMPs overactivity for its inhibitor, brings out the pathologic of cartilage and destroys, and especially can observe in rheumatic arthritis and osteoarthritis.
Under pathologic condition, irreversible articular cartilage degeneration takes place, as at rheumatism, such as in rheumatic arthritis or the osteoarthritis like that.Under these pathologic conditions, cartilage degradation is preponderated, and causes disorganization and loss of function.
At present confirm 20 kinds of different matrix metalloproteinases at least, and be subdivided into four classes, be respectively collagenase, gelatinase, stromelysin and membranous type MMPs (MT-MMPs).
Matrix metalloproteinase-13 (MMP-13) is collagenase type MMP, is the main collagenase of finding during the osteoarthritis, and the chondrocyte causes the pathology of cartilage destruction.
Novel MMP inhibitor need be arranged, especially MMP-13 inhibitor, to prevent and/or to revise the imbalance that the extracellular matrix tissue upgrades, such as sacroiliitis, rheumatic arthritis, osteoarthritis, osteoporosis, periodontopathy, inflammatory bowel, psoriasis, multiple sclerosis, cardiac insufficiency, arteriosclerosis, asthma, chronic obstructive pulmonary disease (COPD), the macular degeneration relevant with the age (age-related macular degeneration, ARMD) and cancer.
The MMP-inhibitor compound is known.Most of these MMP-inhibitor do not have selectivity to single MMP, such as described those inhibitor of people (2000) such as Montana and Baxter (2000) or Clark.
Also need in the prior art that matrix metalloproteinase-13 is had active novel inhibitors, can be used for treating relevant and and the treatment resource of the pathology of related to cancer with the destruction of extracellular matrix to enrich.
Patent application WO9826664 has described the quinazolone compounds that can be used as novel antifungal compound.
The application's compound is new, and is the potent inhibitor of MMP-13.Therefore can be used for treating rheumatic arthritis, osteoarthritis, osteoporosis, periodontopathy, inflammatory bowel, psoriasis, multiple sclerosis, cardiac insufficiency, arteriosclerosis, asthma, chronic obstructive pulmonary disease (COPD), macular degeneration (ARMD) and the cancer relevant with the age.
Summary of the invention
This application has has been confirmed more specifically to be the novel oxo Azabicyclic compounds of selectivity MMP-13 inhibitor for matrix metallo-proteinase inhibitor.
More specifically, the present invention relates to the compound of general formula (I):
Wherein:
● X
1, X
2And X
3Represent nitrogen-atoms or group-CR independently of one another
3, R wherein
3Expression is selected from hydrogen, (C
1-C
6) alkyl, amino, list (C
1-C
6) alkyl amine group, two (C
1-C
6) alkyl amine group, hydroxyl, (C
1-C
6) group of alkoxyl group and halogen,
Condition is a radicals X
1, X
2And X
3In at the most two represent nitrogen-atoms simultaneously,
● G
1Expression is selected from general formula (i/a) and group (i/b):
Wherein:
Group N-R in the carbon atom shack of-numbering 2
1,
-R
4And R
5Identical or different independently of one another, and expression is selected from hydrogen, (C
1-C
6) alkyl, aryl, aryl (C
1-C
6) alkyl, cycloalkyl, cycloalkyl (C
1-C
6) alkyl, heteroaryl, heteroaryl (C
1-C
6) alkyl, Heterocyclylalkyl and Heterocyclylalkyl (C
1-C
6) group of alkyl,
-R
6Expression is selected from following group:
√ hydrogen, trifluoromethyl, OR
7, NR
7R
8, R wherein
7And R
8Identical or different independently of one another, and expression hydrogen or (C
1-C
6) alkyl,
√ (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (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, Heterocyclylalkyl and Heterocyclylalkyl (C
1-C
6) alkyl, these groups are optional to be replaced through one or more group, and described substituting group can be identical or different independently of one another, and expression is selected from halogen, amino, list (C
1-C
6) alkyl amine group, two identical or different independently (C of each moieties
1-C
6) alkyl amine group, cyano group, three halo (C
1-C
6) alkyl, (C
1-C
6) acyl group ,-C (=O) OR
7,-OR
7And-SR
7, R wherein
7As the preamble definition,
● G
2Expression be selected from carbon-to-carbon triple bond ,-CH=C=CH-, C=O, C=S, S (O)
N1Group, wherein n1 represents by 0 to 2 and comprises 0 and 2 integer, and the group of general formula (i/c):
Wherein number 1 carbon atom and connect the dicyclo of general formula (I) compound, Y
1Expression be selected from oxygen, sulphur ,-NH and-N (C
1-C
6) group of alkyl, and Y
2Expression be selected from oxygen, sulphur ,-NH and-N (C
1-C
6) group of alkyl,
● n represents by 0 to 6 and comprises 0 and 6 integer,
● Z
1Expression-CR
9R
10(R wherein
9And R
10Identical or different independently of one another, and expression is selected from hydrogen, (C
1-C
6) alkyl, three halo (C
1-C
6) alkyl, halogen ,-OR
7,-SR
7And-C (=O) OR
7Group, R wherein
7As preamble definition), amino, single (C
1-C
6) alkyl amine group, two (C
1-C
6) alkyl amine group (wherein each moieties is identical or different independently of one another), and
-wherein when n more than or equal to 2 the time, hydrocarbon chain Z
1Optional one or two independence or the conjugated multikey of containing,
-and/or wherein when n more than or equal to 2 the time ,-CR
9R
10One of can choose wantonly by being selected from oxygen, S (O)
N1(wherein n1 such as preamble define) ,-NH and-N (C
1-C
6) group of alkyl replaces,
● A represents to be selected from the group of aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl, and these groups are 5-or 6-person's monocycle or comprise two 5-or the monocyclic dicyclo of 6-person,
● R
1Expression is selected from following group:
-hydrogen,
-(C
1-C
6) alkyl, (C
1-C
6) thiazolinyl, (C
1-C
6) alkynyl, these groups can be chosen wantonly through one or more group and replace, and described substituting group is identical or different independently of one another, is selected from amido, cyano group, three halo (C
1-C
6) alkyl, cycloalkyl ,-C (=O) NR
7R
8,-C (=O) OR
8, OR
8, SR
8Group, R wherein
7And R
8Identical or different independently of one another, and expression hydrogen or (C
1-C
6) alkyl,
-and the group of general formula (i/d):
√ wherein p for by 0 to 8 and comprise 0 and 8 integer,
√ Z
2Expression-CR
11R
12, R wherein
11And R
12Identical or different independently of one another, and expression is selected from hydrogen, (C
1-C
6) alkyl, phenyl, three halo (C
1-C
6) alkyl, halogen, amino, OR
7, SR
7And-C (=O) OR
7Group, R wherein
7Expression hydrogen or (C
1-C
6) alkyl, and
-wherein when p more than or equal to 2 the time, hydrocarbon chain Z
2Optional one or two independence or the conjugated multikey of containing,
-and/or wherein when n more than or equal to 2 the time ,-CR
11R
12One of can choose wantonly by being selected from oxygen, S (O)
N1(wherein n1 such as preamble define) ,-NH ,-N (C
1-C
6) group of alkyl and carbonyl replaces,
√ B represents to be selected from the group of aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl, and these groups are 5-or 6-person's monocycle or the dicyclo be made up of two 5-or 6-person's monocycle,
√ q is for by 0 to 7 and comprise 0 and 7 integer,
The √ group G
3Can be identical or different, and be selected from (C
1-C
6) alkyl, halogen, CN, NO
2, CF
3, OCF
3,-(CH
2) KNR
13R
14,-N (R
13) C (=O) R
14,-N (R
13) C (=O) OR
14,-N (R
13) SO
2R
14,-N (SO
2R
13)
2,-OR
13,-S (O)
K1R
13,-SO
2-N (R
13)-(CH
2)
K2-NR
14R
15,-(CH
2)
kSO
2NR
13R
14,-X
4(CH
2)
kC (=O) OR
13,-(CH
2)
kC (=O) OR
13,-C (=O) O-(CH
2)
K2-NR
13R
14,-C (=O) O-(CH
2)
K2-C (=O) OR
16,-X
4(CH
2)
kC (=O) NR
13R
14,-(CH
2)
kC (=O) NR
13R
14,-R
17-C (=O) OR
13,-X
5-R
18And-C (=O)-R
19-NR
13R
14, wherein:
-X
4Expression is selected from Sauerstoffatom, chooses wantonly through one or two sulphur atom that Sauerstoffatom replaced, nitrogen-atoms (through hydrogen atom or (C
1-C
6) alkyl replaces) and group,
-k is for by 0 to 3 and comprise 0 and 3 integer,
-k1 is for by 0 to 2 and comprise 0 and 2 integer,
-k2 is for by 1 to 4 and comprise 1 and 4 integer,
-R
13, R
14And R
15Identical or different independently of one another, and be selected from hydrogen and (C
1-C
6) alkyl,
-R
16Expression is selected from (C
1-C
6) alkyl ,-R
19-NR
13R
14,-R
19-NR
13-C (=O)-R
19-NR
14R
15And-C (=O) O-R
19-NR
13R
14Group, R wherein
19Expression straight chain or branched chain (C
1-C
6) alkylidene group, and R
13, R
14And R
15As the preamble definition,
-R
17Expression (C
3-C
6) cycloalkyl,
-X
5The expression be selected from singly-bound ,-CH
2-, Sauerstoffatom, optional through one or two sulphur atom that Sauerstoffatom replaced and nitrogen-atoms (through hydrogen atom or (C
1-C
6) alkyl replaces) and group,
-R
18Expression is selected from following group:
O5 or 6-person's monocyclic aryl, heteroaryl, it is chosen wantonly and replaces through one or more group, and described substituting group can be identical or different, and be selected from (C
1-C
6) alkyl, halogen, hydroxyl, cyano group, tetrazyl, amino and-C (=O) OR
7, R wherein
7Expression hydrogen or (C
1-C
6) alkyl,
O5-or 6-person's monocyclic cycloalkyl, Heterocyclylalkyl, it is chosen wantonly and replaces through one or more group, and described substituting group can be identical or different, and be selected from (C
1-C
6) alkyl, halogen, hydroxyl, oxo, cyano group, tetrazyl, amino and-C (=O) OR
7, R wherein
7Expression hydrogen or (C
1-C
6) alkyl,
● m is for by 0 to 7 and comprise 0 and 7 integer,
● radicals R
2Identical or different independently of one another, and be selected from (C
1-C
6) alkyl, halogen ,-CN, NO
2, SCF
3,-CF
3,-OCF
3,-NR
7R
8,-OR
8,-SR
8,-SOR
8,-SO
2R
8,-(CH
2)
kSO
2NR
7R
8,-X
7(CH
2)
kC (=O) OR
8,-(CH
2)
kC (=O) OR
8,-X
7(CH
2)
kC (=) NR
7R
8,-(CH
2)
kC (=) NR
7R
8And-X
8-R
20, wherein:
-X
7Expression is selected from oxygen, sulphur (choose wantonly and replace through one or two Sauerstoffatom) and nitrogen (through hydrogen or (C
1-C
6) alkyl replaces) and group,
-k is for by 0 to 3 and comprise 0 and 3 integer,
-R
7And R
8Identical or different independently of one another, and be selected from hydrogen and (C
1-C
6) alkyl,
-X
8The expression be selected from singly-bound ,-CH
2-, Sauerstoffatom, optional through one or two sulphur atom that Sauerstoffatom replaced and nitrogen-atoms (through hydrogen atom or (C
1-C
6) alkyl replaces),
-R
20Expression 5-or 6-person's monocyclic aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl, it is chosen wantonly and replaces through one or more group, and described substituting group can be identical or different, and be selected from (C
1-C
6) alkyl, halogen, hydroxyl and amino, and when this ring during for heterocycle, it comprises 1 to 4 heteroatoms that is selected from nitrogen, oxygen and sulphur,
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
According to first embodiment, the present invention relates to the compound of general formula (I), wherein:
● G
2Expression is selected from C=O, C=S, S (O)
N1Group, wherein n1 represents by 0 to 2 and comprises 0 and 2 integer, or the group of following formula (i/c):
Wherein number 1 carbon atom and connect the dicyclo of the compound of general formula (I), Y
1Expression be selected from oxygen, sulphur ,-NH and-N (C
1-C
6) group of alkyl, and Y
2Expression be selected from oxygen, sulphur ,-NH and-N (C
1-C
6) group of alkyl,
● X
1, X
2, X
3, G
1, n, Z
1, A, R
1, m and R
2As definition in the general formula (I).
According to second embodiment, the present invention relates to the compound of general formula (I), wherein:
● G
2The expression carbon-to-carbon triple bond,
● n represents by 1 to 6 and comprises 1 and 6 integer,
● X
1, X
2, X
3, G
1, Z
1, A, R
1, m and R
2As definition in the general formula (I).
According to the 3rd embodiment, the present invention relates to the compound of general formula (I), wherein:
● G
2The expression carbon-to-carbon triple bond,
● n is 0,
● Z
1Do not exist,
● A represents to be selected from the group of heteroaryl, cycloalkyl, Heterocyclylalkyl, and these groups are 5-or 6-person's monocycle or the dicyclo be made up of two 5-or 6-person's monocycle,
● X
1, X
2, X
3, G
1, R
1, m and R
2As definition in the general formula (I).
According to the 4th embodiment, the present invention relates to the compound of general formula (I), wherein:
● G
2The expression carbon-to-carbon triple bond,
● n is 0,
● Z
1Do not exist,
● A represents phenyl,
● R
1The group of expression general formula (i/d):
√ wherein p for by 0 to 8 and comprise 0 and 8 integer,
√ Z
2Expression-CR
11R
12, R wherein
11And R
12Identical or different independently of one another, and expression is selected from hydrogen, (C
1-C
6) alkyl, phenyl, three halo (C
1-C
6) alkyl, halogen, amino, OR
7, SR
7And-C (=O) OR
7Group, R wherein
7Expression hydrogen or (C
1-C
6) alkyl, and
-wherein when p more than or equal to 2 the time, hydrocarbon chain Z
2Optional one or two independence or the conjugated multikey of containing,
-and/or wherein when n more than or equal to 2 the time ,-CR
11R
12One of can choose wantonly by being selected from oxygen, S (O)
N1(wherein n1 such as preamble define) ,-NH ,-N (C
1-C
6) group of alkyl and carbonyl replaces,
√ B represents phenyl,
√ q is for by 1 to 7 and comprise 1 and 7 integer,
The √ group G
3Can be identical or different, and be selected from-(CH
2)
kNR
13R
14,-N (R
13) C (=O) OR
14,-N (R
13) SO
2R
14,-N (SO
2R
13)
2,-S (O)
kR
13,-SO
2-N (R
13)-(CH
2)
K2-NR
14R
15,-(CH
2)
kSO
2NR
13R
14,-X
4(CH
2)
kC (=O) OR
13,-(CH
2)
kC (=O) OR
13,-C (=O) O-(CH
2)
K2-NR
13R
14,-C (=O) O-(CH
2)
K2-C (=O) OR
16,-X
4(CH
2)
kC (=O) NR
13R
14,-(CH
2)
kC (=O) NR
13R
14,-R
17-C (=O) OR
13,-X
5-R
18,-C (=O)-R
19-NR
13R
14And-X
6-R
21, wherein:
-X
4Expression is selected from Sauerstoffatom, chooses wantonly through one or two sulphur atom that Sauerstoffatom replaced, nitrogen-atoms (through hydrogen atom or (C
1-C
6) alkyl replaces) and group,
-k is for by 0 to 3 and comprise 0 and 3 integer,
-k1 is for by 1 to 2 and comprise 1 and 2 integer,
-k2 is for by 1 to 4 and comprise 1 and 4 integer,
-R
13, R
14And R
15Identical or different independently of one another, and be selected from hydrogen and (C
1-C
6) alkyl,
-R
16Expression is selected from (C
1-C
6) alkyl ,-R
19-NR
13R
14,-R
19-NR
13-C (=O)-R
19-NR
14R15 and-C (=O) O-R
19-NR
13R
14Group, R wherein
19Expression straight chain or branched chain (C
1-C
6) alkylidene group, and R
13, R
14And R
15As the preamble definition,
-R
17Expression (C
3-C
6) cycloalkyl,
-X
5The expression be selected from singly-bound ,-CH
2-, Sauerstoffatom, optional through one or two sulphur atom that Sauerstoffatom replaced and nitrogen-atoms (through hydrogen atom or (C
1-C
6) alkyl replaces) and group,
-R
18Expression is selected from the group of heteroaryl, cycloalkyl, Heterocyclylalkyl, and these groups are 5 or 6-person's monocycle or the dicyclo is made up of two 5-or 6-person's monocycle, and it is chosen wantonly and replaces through one or more group, and described substituting group can be identical or different, and be selected from (C
1-C
6) alkyl, halogen, hydroxyl, oxo, cyano group, tetrazyl, amino and-C (=O) OR
7, R wherein
7Expression hydrogen or (C
1-C
6) alkyl,
-X
6Expression is selected from-CH
2-, optional through one or two sulphur atom that Sauerstoffatom replaced and nitrogen-atoms (through hydrogen atom or (C
1-C
6) alkyl replaces) and group,
-R
21Expression is optional through the phenyl that one or more group replaced, and described substituting group can be identical or different, and be selected from (C
1-C
6) alkyl, halogen, hydroxyl, cyano group, tetrazyl, amino and-C (=O) OR
7, R wherein
7Expression hydrogen or (C
1-C
6) alkyl,
● and X
1, X
2, X
3, G
1, m and R
2As definition in the general formula (I).
The preferred radicals R of the present invention
1Group for general formula (i/d):
Z wherein
2, p, B, G
3And define in q such as general formula (I) compound.
More specifically, more preferably substituent R of the present invention
1Group for general formula (i/d):
Z wherein
2Expression-CR
11R
12, R wherein
11And R
12Each represents hydrogen atom, and p, B, G
3And define in q such as general formula (I) compound.
More specifically, more preferred substituents R of the present invention
1Group for general formula (i/d):
Wherein p is 1, and Z
2, B, G
3And define in q such as general formula (I) compound.
More specifically, more preferred substituents R of the present invention
1Group for general formula (i/d):
Wherein B represents phenyl, and q equals 0 or 1, and G
3(when existing) expression is selected from OR
13, halogen, S (O)
K1R
13And (CH
2)
kC (=O) OR
13Group, R wherein
13Expression hydrogen atom or (C
1-C
6) alkyl, k is 0, and k1 is 2, and Z
2, define in p such as general formula (I) compound.
The present invention also relates to the compound of a kind of general formula (I), wherein G
1The group of expression general formula (i/a), wherein R
4Expression hydrogen atom or methyl, or the group of general formula (i/b), wherein R
4And R
5Identical and respectively represent hydrogen atom or methyl, and R
6Expression hydrogen atom or methyl, and X
1, X
2, X
3, G
2, Z
1, n, m and R
2As definition in the general formula (I).
Preferred The compounds of this invention is the compound of general formula (I), wherein X
1Expression group-CR
3, R wherein
3The expression hydrogen atom, X
2Expression nitrogen-atoms or group-CR
3, R wherein
3Expression hydrogen atom, and X
3Expression group-CR
3, R wherein
3The expression hydrogen atom.
Other preferred The compounds of this invention are G wherein
2The compound of the group of expression carbon-to-carbon triple bond or general formula (i/c), wherein Y
1Expression Sauerstoffatom, and Y
2Expression group-NH.
Preferred The compounds of this invention is general formula (I) compound, wherein Z
1Expression-CR
9R
10, R wherein
9And R
10Represent hydrogen atom separately, and n is 1.
Particularly preferred The compounds of this invention represents to be selected from the group of phenyl and pyridyl for A wherein, and m is 0 or 1, and R
2Expression (C
1-C
6) compound of alkoxyl group or hydrogen atom.
The invention particularly relates to the compound of following general formula (I):
3-(4-methoxyl group-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides
3-(4-methoxyl group-benzyl)-2-methyl-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides, hydrochloride
3-(4-methoxyl group-benzyl)-1-methyl-4-oxo-1,2,3,4-tetrahydrochysene-quinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides
3-(4-methoxyl group-benzyl)-1,2,2-trimethylammonium-4-oxo-1,2,3,4-tetrahydrochysene-quinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides
4-[6-(4-methoxyl group-benzyl amido formyl radical)-4-oxo-1,4-dihydro-2H-quinazoline-3-ylmethyl]-phenylformic acid
4-[6-(4-methoxyl group-benzyl amido formyl radical)-1-methyl-4-oxo-1,4-dihydro-2H-quinazoline-3-ylmethyl]-methyl benzoate
4-[6-(4-methoxyl group-benzyl amido formyl radical)-1-methyl-4-oxo-1,4-dihydro-2H-quinazoline-3-ylmethyl]-phenylformic acid
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 3-methoxy-benzyl acid amides
3-(4-methylsulfonyl)-benzyl-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides
4-oxo-3-[4-(tetramethyleneimine-1-alkylsulfonyl)-benzyl]-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides
4-[6-(3-methoxyl group-benzyl amido formyl radical)-4-oxo-4H-quinazoline-3-ylmethyl]-phenylformic acid
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid (2-methoxyl group-pyridin-4-yl methyl)-acid amides
3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 3-methoxyl group-benzyl acid amides,
And 3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 4-methoxyl group-benzyl acid amides.
Other go back preferred compound has:
3-(3,4-two fluoro-benzyls)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid (2-methoxyl group-pyridin-4-yl methyl)-acid amides
3-(3,4-two fluoro-benzyls)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides.
The present invention especially also relates to following general formula (I) compound:
3-(4-luorobenzyl)-6-(3-phenyl-third-1-alkynyl)-3H-quinazoline-4-one,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-methyl benzoate,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid,
3-(4-luorobenzyl)-6-(3-phenyl-third-1-alkynyl)-3H-pyrido [3,4-d] pyrimidin-4-one,
4-[6-(3-phenyl-third-1-alkynyl)-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl] methyl benzoate,
4-[6-(3-phenyl-third-1-alkynyl)-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl] phenylformic acid,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H quinazoline-3-ylmethyl]-phenylformic acid,
4-{6-[3-(4-p-methoxy-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzamide,
And 3-[(3,5-two fluoro-4-hydroxyls)-benzyl]-6-(3-phenyl-third-1-alkynyl)-3H-quinazoline-4-one.
Other go back preferred compound has:
4-[6-(3-imidazoles-1-base-third-1-alkynyl)-4-oxo-4H-quinazoline-3-ylmethyl]-phenylformic acid,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzsulfamide,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzonitrile,
3-(3-chloro-benzyl)-6-(4-phenyl-Ding-1-alkynyl)-3H-quinazoline-4-one,
3-(3-chloro-benzyl)-6-(3-phenyl-third-1-alkynyl)-3H-quinazoline-4-one,
4-[4-oxo-6-(3-pyrazol-1-yl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid,
6-(3-phenyl-third-1-alkynyl)-3-[4-(1H-tetrazolium-5-yl)-benzyl]-the 3H-quinazoline-4-one,
3-(3,4-two fluoro-benzyls)-6-[3-(pyridin-4-yl oxygen)-third-1-alkynyl]-the 3H-quinazoline-4-one,
3-(3,4-two fluoro-benzyls)-6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
N-{4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenyl }-ethanamide,
3-(3,4-two chloro-benzyls)-6-(3-phenyl-third-1-alkynyl)-3H-quinazoline-4-one,
3-(4-ethanoyl-benzyl)-6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
6-(3-phenyl-third-1-alkynyl)-3-pyridin-4-yl methyl-3H-quinazoline-4-one
6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-3-pyridin-4-yl methyl-3H-quinazoline-4-one.
Most preferred is the listed compound of following table, and it is with reference to after a while embodiment among the application.
The optical isomer of preferred compound of the present invention, N-oxide compound and form integral part of the present invention with additive salt that pharmaceutically useful acid or alkali form.
The present invention also relates to a kind of pharmaceutical composition, its general formula (I) compound that comprises significant quantity is with as activeconstituents, and one or more pharmaceutically useful vehicle or carrier.
Another embodiment of the present invention relates to general formula (I) compound in the purposes that is used for preparing the pharmaceutical prod that uses for the treatment disease, and described treatment relates to and suppresses especially the 13rd type matrix metalloproteinase of matrix metalloproteinase.
The present invention also relates to a kind of method for the treatment of ill life entity, described treatment relates to the 13rd type matrix metalloproteinase of inhibition matrix metalloproteinase-especially, and this method comprises that the patient to needs uses the general formula of significant quantity (I) compound.
Preferred therapeutic method of the present invention is that treatment is selected from following disease: sacroiliitis, rheumatic arthritis, osteoarthritis, osteoporosis, periodontopathy, inflammatory bowel, psoriasis, multiple sclerosis, cardiac insufficiency, arteriosclerosis, asthma, chronic obstructive pulmonary disease, macular degeneration and the cancer relevant with the age.
More specifically, preferred therapeutic method of the present invention is the disease that treatment is selected from sacroiliitis, osteoarthritis and rheumatic arthritis.
Detailed Description Of The Invention
Compound provided by the present invention is the defined compound of general formula (I).In the general formula (I), be construed as:
-(C
1-C
6) alkyl represents to contain the straight or branched group of 1 to 6 carbon atom; The unrestricted example of this group has methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, neo-pentyl, hexyl,
-(C
2-C
6) thiazolinyl represents to contain the straight or branched group of 2 to 6 carbon atoms and one or more pair key; The unrestricted example of this group has vinyl, allyl group, 3-butene-1-Ji, 2-methyl-butene-1-Ji, hexenyl,
-(C
2-C
6) alkynyl represents to contain the straight or branched group of 2 to 6 carbon atoms and one or more three key; The unrestricted example of this group has ethynyl, proyl, 3-butine-1-base, 2-methyl-1-butene alkynes-1-base, hexin base,
-(C
1-C
6) alkoxyl group means and the Sauerstoffatom key connects aforesaid alkyl; The unrestricted example of this group has methoxyl group, oxyethyl group, positive propoxy, tert.-butoxy,
-single (C
1-C
6) alkyl amine group represents by an aforementioned (C
1-C
6) amido that replaces of alkyl; The unrestricted example of this group has methyl amido, isobutyl-amido, ethyl amido,
-two (C
1-C
6) alkyl amine group represents by two aforementioned (C
1-C
6) amido that alkyl replaces, each alkyl is identical or different; The unrestricted example of this group is dimethyl amido, diethyl amido,
-aryl represents to contain the aromatic monocyclic or the bicyclic system of 5 to 10 carbon atoms, if bicyclic system, then wherein a ring has aromaticity, and another ring can be aromaticity or partial hydrogenation; The unrestricted example of this group has phenyl, naphthyl, indenyl, benzocyclobutane thiazolinyl,
-heteroaryl represents that wherein 1 to 4 carbon atom is by 1 to 4 aforementioned aryl of heteroatoms institute metathetical that is selected from oxygen, sulphur and nitrogen; The unrestricted example of this group has furyl, thienyl, pyrryl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indyl, quinolyl, isoquinolyl, benzo dioxolyl, benzo dioxy cyclohexenyl, benzo [1,2,5] thiadiazolyl group, benzo [1,2,5] oxadiazole bases.
-cycloalkyl represents to contain the monocycle or the bicyclic system of 3 to 10 carbon atoms, this system be saturated or part undersaturated, but do not have aromaticity; The unrestricted example of this group has cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ring octyl group, suberyl, adamantyl, decahydro naphthyl, norcamphyl,
-Heterocyclylalkyl represents that wherein 1 to 4 carbon atom is the aforementioned cycloalkyl of heteroatoms institute metathetical that is selected from oxygen, sulphur and nitrogen by 1 to 4,
-dicyclo is represented two condensed monocycles, and
-three halo (C
1-C
6) alkyl represents to contain the aforesaid alkyl of three halogens; The unrestricted example of this group is a trifluoromethyl, 2,2, the 2-trifluoroethyl,
-(C
1-C
7) acyl group represents aforesaid alkyl or the aryl with the carbonyl bonding; The unrestricted example of this group is ethanoyl, B carbonyl, benzoyl,
-multikey is represented two keys or triple bond,
-halogen atom is represented fluorine, chlorine, bromine or iodine,
-optical isomer is represented racemic mixture, enantiomer and diastereomer.
The present invention also relates to the pharmaceutically useful salt of general formula (I) compound.The comment of pharmaceutically useful salt is with reference to J.Pharm.Sci., and 1977,66,1-19.
Pharmaceutically useful acid means the inorganic or organic acid of the nontoxic salt of can deriving.The unrestricted example that wherein can mention has hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, citric acid, acetate, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, xitix, oxalic acid, methylsulfonic acid, dextrocamphoric acid, phenylformic acid, toluenesulphonic acids etc.
Pharmaceutically useful alkali means the inorganic or organic bases of the nontoxic salt of can deriving.Wherein, the unrestricted example that can mention has sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, tert-butylamine, dibenzyl-ethylenediamin, piperidines, tetramethyleneimine, benzyl amine, quaternary ammonium hydroxide etc.
The present invention also relates to a kind of preparation general formula (I) bonded method, it uses general formula (II) compound as initial substance:
X wherein
1, X
2, X
3And Y
1Be have with general formula (I) compound in identical definition, and T represents group (C
1-C
6) alkyl,
General formula (II) compound uses general formula (III) compound to handle:
Z wherein
1, Y
2, R
2, A, n and m have with general formula (I) compound in identical definition,
By in the presence of diisopropylethylamine and solvent, activate this acid function with activator, produce logical
The compound of formula (IV):
X wherein
1, X
2, X
3, Y
1, T, Z
1, Y
2, R
2, A, n and m such as preamble define,
Ester group is through hydrolysis in general formula (IV) compound, and the compound of gained is at alkali and general formula R
1-NH
2(R wherein
1As defining in general formula (I) compound) primary amine exist down with Treatment with activating agent,
Produce logical formula V compound:
X wherein
1, X
2, X
3, Y
1, Y
2, Z
1, R
2, A, n and m such as preamble define,
Should logical formula V compound be to handle through following manner:
● under heating condition, use triethyl orthoformate to handle, produce the compound of general formula (I/a), it is the special case of general formula (I):
X wherein
1, X
2, X
3, Y
1, Y
2, Z
1, R
2, R
1, A, n and m such as preamble define,
● or under heating condition, in the presence of acid, with general formula (VI) compound treatment:
R wherein
4Have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/b), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, Y
1, Y
2, Z
1, R
2, R
1, R
4, A, n and m such as preamble define,
● or under alkaline condition, use general formula (VII) compound treatment:
R wherein
4And R
5Have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/c), it is the special case of general formula (I):
X wherein
1, X
2, X
3, Y
1, Y
2, Z
1, R
2, R
1, R
4, R
5, A, n and m such as preamble define,
This general formula (I/c) compound is chosen wantonly in the presence of general formula (VIII) compound, uses hydride to handle:
R
6-Hal (VIII)
R wherein
6Have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/d), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, Y
1, Y
2, Z
1, R
2, R
1, R
5, R
5, R
6, A, n and m such as preamble define,
General formula (I/a), (I/b), (I/c) and compound component part The compounds of this invention (I/d), it optionally carries out purifying according to conventional purification technique, optionally be separated into different isomer, and optionally use pharmaceutically useful acid or alkali to change into additive salt or change into its N-oxide compound according to conventional isolation technique.
The present invention also relates to a kind of method for preparing general formula (I) compound, it uses general formula (X) compound as initial substance:
X wherein
1, X
2And X
3Have with general formula (I) compound in identical definition, and Hal represents halogen atom,
This general formula (X) compound uses the derivative of phosgene to handle in first step, to produce the compound of general formula (XI):
X wherein
1, X
2, X
3Reach Hal such as preamble and define,
This general formula (XI) compound uses general formula R in alkaline medium
1The primary amine of-NH (R wherein
1Have with general formula (I) compound in identical definition) handle, produce the compound of general formula (XII):
X wherein
1, X
2, X
3, R
1Reach Hal such as preamble and define,
This general formula (XII) compound is handled in such a way:
● under heating condition, use triethyl orthoformate to handle, to produce the compound of general formula (XIII/a):
X wherein
1, X
2, X
3, R
1Reach Hal such as preamble and define,
● or under heating condition, in the presence of acid, use general formula (VI) compound to handle:
R wherein
4Have with general formula (I) compound in identical definition,
Produce the compound of general formula (XIII/b):
X wherein
1, X
2, X
3, Hal, R
1And R
4As the preamble definition,
● or under alkaline condition, use general formula (VII) compound treatment:
R wherein
4And R
5Have with general formula (I) compound in identical definition,
Produce the compound of general formula (XIII/c):
X wherein
1, X
2, X
3, Hal, R
1, R
4And R
5As the preamble definition,
The compound of this general formula (XIII/c) is chosen wantonly in the presence of general formula (VIII) compound, uses hydride to handle:
R
6-Hal (VIII)
R wherein
6Have with general formula (I) compound in identical definition, and Hal is halogen,
Produce the compound of general formula (XIII/d), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, Hal, R
1, R
4, R
5And R
6As the preamble definition,
General formula (XIII/a), (XIII/b), (XIII/c) and compound (XIII/d) constitute the compound of general formula (XIII/e):
X wherein
1, X
2, X
3, Hal, R
1And G
1Suc as formula defining in (I) compound,
This general formula (XIII/e) compound uses general formula (XIV) compound to handle under via palladium-catalyzed alkynyl condition:
Z wherein
1, R
2, A, n and m have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/e), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, R
1, G
1, Z
1, R
2, A, n and m have with general formula (I) compound in identical definition,
General formula (I/e) compound component part The compounds of this invention, it is optionally to carry out purifying according to conventional purification technique, optionally be separated into different isomer, and optionally use pharmaceutically useful acid or alkali to change into additive salt or change into its N-oxide compound according to conventional isolation technique.
Another kind is to be described in the following schema I from the mode that general formula (XI) compound makes general formula (XIII/a) compound:
Schema 1
X wherein
1, X
2, X
3, R
1Reaching Hal such as preamble defines.
In first step, general formula (XI) compound is to handle with ammonium hydroxide aqueous solution, produces general formula (XI/a) compound, and it reacts with triethyl orthoformate in the presence of the acid such as tosic acid (PTSA) of catalytic amount.The 3H-quinazoline-4-one (XI/b) of gained is condensed to general formula R in alkaline medium
1The compound of-Hal (R wherein
1Definition and Hal as general formula (I) compound represent halogen) on, to produce the compound of general formula (XIII/a).
The present invention also relates to a kind of method for preparing general formula (I) compound, it uses general formula (XIII/e) compound as initial substance:
X wherein
1, X
2, X
3, R
1And G
1As defining in general formula (I) compound, and Hal be halogen former in,
General formula (XIII/e) compound is at two (triphenyl phosphine) palladiums of dichloro, cupric iodide and N, and N '-diisopropylethylamine exists down, in dimethyl formamide, is condensed on the compound of general formula (XV):
Z wherein
1, R
2, A, n and m have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/e), it is the special case of general formula (I) compound:
X wherein
l, X
2, X
3, R
1, G
1, Z
1, R, A, n and m have with general formula (I) compound in identical definition.
The present invention also relates to a kind of method for preparing general formula (I) compound, it uses general formula (XIII/e) compound as initial substance:
X wherein
1, X
2, X
3, R
1And G
1As defining in general formula (I) compound, and Hal is halogen atom,
The compound of general formula (XIII/e) in the presence of protic solvent such as methyl alcohol and catalytic amount palladium, with reaction of carbon monoxide, produces the compound of general formula (XVI) in alkaline media:
X wherein
1, X
2, X
3, R
1And G
1As defining in general formula (I) compound,
The hydrolysis in alkaline medium of general formula (XVI) compound, the compound of generation general formula (XVII):
X wherein
1, X
2, X
3, R
1And G
1As defining in general formula (I) compound,
The compound of general formula (XVII) in the presence of Mukayama reagent, is condensed on general formula (XVIII) compound in alkaline medium:
Z wherein
1, R
2, A, n and m have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/f), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, Z
1, R
2, R
1, A, n and m define as preamble,
The compound component part The compounds of this invention of general formula (I/f), it is optionally to carry out purifying according to conventional purification technique, optionally be separated into different isomer, and optionally use pharmaceutically useful acid or alkali to change into additive salt or change into its N-oxide compound according to conventional isolation technique.
The present invention also relates to a kind of method for preparing general formula (I) compound, it uses general formula (XIX) compound as initial substance:
Wherein Hal represents halogen atom,
General formula (XIX) compound reacts in the presence of polar solvent such as 2-methoxyl group second-1-alcohol in the presence of carbonamidine, produces the compound of general formula (XX):
Wherein Hal such as preamble define,
The compound of general formula (XX) uses general formula R in alkaline medium
1-Hal compound (R wherein
1As defining in general formula (I) compound, and Hal represents halogen atom) handle, produce the compound of general formula (XXI):
Wherein Hal and R
1As the preamble definition,
The compound of general formula (XXI) is in alkaline medium, at alcoholic solvent such as methyl alcohol and catalytic amount palladium such as PdCl
2(dppf) exist down, react, produce the compound of general formula (XXII) with carbon monoxide:
R wherein
1As the preamble definition,
The compound of general formula (XXII) in the presence of trimethyl aluminium, and the compound condensation of general formula (XVIII):
Z wherein
1, R
2, A, n and m have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/g), it is the special case of general formula (I) compound:
Z wherein
1, R
2, R
1, A, n and m be as preceding definition,
The compound component part The compounds of this invention of general formula (I/g), it is optionally to carry out purifying according to conventional purification technique, optionally be separated into different isomer, and optionally use pharmaceutically useful acid or alkali to change into additive salt or change into its N-oxide compound according to conventional isolation technique.
The The compounds of this invention that exists with the non-enantiomer mixture form uses conventional isolation technique such as chromatographic separation to become the pure substance form.
As mentioned before, general formula of the present invention (I) compound is a matrix metallo-proteinase inhibitor, especially the inhibitor of enzyme MMP-13.
Thus, it is proposed to be used in and treats disease or the disease symptoms that relates to by the treatment that is suppressed by MMP-13 to carry out.For example, The compounds of this invention can be proposed and be used in any pathological condition that extracellular matrix disorganization takes place in treatment, especially such as sacroiliitis, rheumatic arthritis, osteoarthritis, osteoporosis, periodontopathy, inflammatory bowel, psoriasis, multiple sclerosis, must dirty insufficiency of function, arteriosclerosis, asthma, chronic obstructive pulmonary disease, the macular degeneration relevant and the pathological condition of cancer with the age.
The invention still further relates to a kind of pharmaceutical composition, it comprises the additive salt of at least a general formula (I) compound, its isomer, its N-oxide compound or itself and pharmaceutically useful acid or alkali, with as activeconstituents, this activeconstituents is independent use, or, inertia pharmaceutically useful with one or more, nontoxic vehicle or carrier are used in combination.
In pharmaceutical composition of the present invention, mention especially be those be suitable for per os, parenteral (intravenously, intramuscular or subcutaneous), through skin or transdermal, intravaginal, rectum, intranasal, through tongue, through cheek, through the composition of eye or respiratory system administration.
The pharmaceutical composition of the present invention that carries out the parenteral injection use is particularly including water-based and non-aqueous sterile solution, dispersion liquid, suspension and emulsion, and the sterilized powder that is used to reconstruct injection solution or dispersion liquid use.
Comprise lozenge or drageeing, Sublingual tablet, powder capsule (sachet), gelatine capsule and particle for peroral administration solid pharmaceutical composition of the present invention, per os, intranasal, through the fluid composition of cheek or administration through eye particularly including emulsion, solution, suspension, drops, syrup and aerosol.
For the preferred suppository of pharmaceutical composition of rectum or vagina administration, and through the composition of skin or transdermal administration particularly including powder, aerosol, ointment, ointment, gel and application.
Aforementioned pharmaceutical composition is explanation the present invention, but unrestricted.
In pharmaceutically useful, the inertia that can mention, non-toxic excipients or the carrier, unrestricted example has thinner, solvent, sanitas, wetting agent, emulsifying agent, dispersion agent, tackiness agent, swelling agent, disintegrating agent, delayed-action activator, lubricant, sorbent material, suspending agent, tinting material, perfume compound etc.
Spendable dosage is decided on the character of patient's age and body weight, route of administration, employed pharmaceutical composition, disease and seriousness and any treatment of making up.Dosage range be 2 milligrams to 1 gram every day, divide one or multiple dosing.Said composition prepares by this area those skilled in the art's known method, comprises the active principal constituent (general formula (I) compound) of 0.5 to 60 weight % and pharmaceutically acceptable vehicle or the carrier of 40 weight % to 99.5 weight % usually.
Following examples are explanation the present invention, but restriction absolutely not.
Employed initial substance is known or passes through known operation method preparation generation.Various preparation produces the synthetic intermediate that can be used for preparing The compounds of this invention.Part is a compounds in these intermediates.
The structure of the compound described in embodiment and the preparation example is determined according to general spectroscopic techniques (infrared, nucleus magnetic resonance, mass spectrum etc.).
In preparation example and embodiment, be construed as:
DMF represents dimethyl formamide,
THF represents tetrahydrofuran (THF),
DMSO represents dimethyl sulfoxide (DMSO),
TOTU represents O-(ethoxycarbonyl) cyano methyl amido)-N-N-N '-N '-tetramethyl-urea fluoroborate,
DIPEA represents diisopropylethylamine.
Embodiment
Preparation example 1:
4-amino-3-[(4-methoxyl group)-benzyl amido formyl radical]-1-carboxylic acid 4-methoxyl group-benzyl acid amides
Step 1:4-amino-isophthalic acid
With 6.3 gram (150 mmole) lithium hydroxide H
2O joins in 15.7 gram (75 mmole) 4-amino-stirring solution of isophthalic acid methyl esters in 300 milliliters of dioxs and 1200 ml waters.With reaction mixture 100 ℃ of heating 1 hour, cooling, and add dense HCl and be acidified to pH=1.Leach the throw out of gained, washing, and dry under vacuum, the required compound of generation 13 grams (productive rate=95.7%).
N.M.R(DMSO-d
6)
1Hδ(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-methoxyl group)-benzyl amido formyl radical]-phenyl-1-carboxylic acid 4-methoxyl group-benzyl acid amides
2.25 gram (16.5 mmole) 4-methoxy-benzyl amine, 5.4 gram (16.5 mmole) TOTU and 5.4 milliliters of (3.9 grams, 30 mmoles) DIPEA are joined in the stirring solution of compound in 100 milliliters of DMF of 2.7 gram (15 mmole) step 1 gained successively.With the reaction mixture stirred overnight at room temperature, go down to desolventize in vacuum afterwards.Crude mixture is dissolved in the methylene dichloride, uses 1N HCl and 1N HaOH to wash successively.The decant after separating is with organic phase Na
2SO
4Drying, vacuum concentration.Crude product is by chromatography purification, and is fixed from the mixture of methylene dichloride and ether, produces the required compound of 3.1 grams (productive rate=49.3%).
N.M.R(DMSO-d
6)
1Hδ(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)。
Preparation example 2:
4-{[2-amino-5-(4-methoxyl group-benzyl amido formyl radical)-benzoylamino]-methyl)-methyl benzoate
Step 1:
6-amino-N-(4-methoxyl group-benzyl)-isophthalic acid methyl esters
6.56 gram (20 mmole) TOTU and 2.6 milliliters of (2.74 grams, 20 mmoles) 4-methoxy-benzyl amine are joined in 4.2 gram (18.1 mmole) 4-amino-3-methyl carboxylic acids ester-stirring solution of 1-phenyl carboxylic acid in 150 milliliters of dry DMF.Mixture 0 ℃ of cooling down, is added 9.5 milliliters of (7.02 grams, 54.3 mmoles) DIPEA.With reaction mixture stirred overnight at room temperature, vacuum concentration.Residue is dissolved in 150 milliliters of methylene dichloride, with 100 milliliters of saturated NaHCO
3Solution washing.Organic layer drying, and vacuum concentration.On silica gel, after the chromatography, separate obtaining 3.5 gram (productive rate=62%) required compounds.
TLC：CH
2Cl
2/MeOH?90/10Rf＝0.80
N.M.R(DMSO-d
6)
1Hδ(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-methoxyl group-benzyl)-different carboxyl benzamide (isophthalamic acid)
With 0.3 gram (7 mmole) lithium hydroxide H
2O joins in the stirring solution of compound in 10 milliliters of dioxs and 40 ml waters of 1.1 gram (3.5 mmole) abovementioned steps, 2 gained.With reaction mixture refluxed heating 2 hours, cooling added dense HCl with acidifying under pH=1.Leach the gained throw out, drying produces required compound.
N.M.R(DMSO-d
6)
1Hδ(ppm)：3.70(s，3H)；4.35(d，2H)；6.75(d，1H)；6.85(d，2H)；7.20(d，21H)；7.75(dd，1H)；8.30(s，1H)；8.65(t，1H)。
Step 3:
4-{[2-amino-5-(4-methoxyl group-benzyl amido formyl radical)-benzoylamino]-methyl }-methyl benzoate
Required compound is according to the described method of the step 1 of aforementioned preparation example 2, uses the starter compound of abovementioned steps 2 gained and makes as 4-(amino methyl) the methyl benzoate hydrochloride of reactant.The mixture that uses methylene dichloride/ether by chromatography on silica gel is as eluent and purifying.
N.M.R(DMSO-d
6)
1Hδ(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)；.45(t，1H)；8.90(t，1H)。
Preparation example 3:
3-(4-luorobenzyl)-6-iodo-3H-quinazoline-4-one
Step 1:
6-iodo-1H-benzo [a] [1,3] oxazine-2,4-diketone
To 2-amino-5-iodo-benzoic acid (4.9 gram, 18.0 mmoles) at H
2Add diox (50 milliliters) in the suspension of O (20 milliliters) and dense HCl (5 milliliters), until obtaining settled solution.Drip pure trichloromethylchloroformate (5.95 grams, 30.0 mmoles) (cooling sometimes is not to make the solution boiling), produce white depositions.After the stirring at room 10 minutes, add H
2O (about 100 milliliters) leaches throw out, with a large amount of H
2The O washing.Vacuum-drying, and the required product of generation white crystals (5.2 grams, quantitatively).
N.M.R(DMSO-d
6)
1Hδ(ppm)：6.93(d.J＝8.6Hz，1H)，8.00(dd，J＝8.6m2.0Hz，1H)，8.10(d，1J＝2.0Hz，1H)，11.8(s，1H)；
MS(APCI)，m/z?288.0(M-1)。
Step 2:
2-amino-N-(4-luorobenzyl)-5-iodo-benzamide
In the 50 ℃ solution of compound (2.1 grams, 7.27 mmoles) in DMF (20 milliliters) of abovementioned steps 1 gained, drip pure 4-luorobenzyl amine (1.18 grams, 9.45 mmoles).Reaction stirring at room 10 minutes finds to have the bubble (CO of emerging this moment
2), the TLC demonstration reacts completely.Reaction content poured into CH is housed
2Cl
2And H
2In the separating funnel of O.After separating, organic layer is with H
2O (3 * 50 milliliters) and salt solution (50 milliliters) washing.Dry (Na
2SO
4), filtration and vacuum concentration, produce white solid, it uses flash chromatography purifying, produces the required compound (2.5 grams, 93%) of white solid.
N.M.R(DMSO-d
6)
1Hδ(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-luorobenzyl)-6-iodo-3H-quinazoline-4-one
The TsOH that in the triethyl orthoformate solution of the compound of abovementioned steps 2 gained (2.69 grams, 7.27 mmoles), adds catalytic amount.Solution was refluxed 5 hours, be cooled to room temperature.Vacuum is removed after all volatile matters, and residue uses the flash chromatography purifying, produces the required quinazoline of brown solid.Obtain the required compound (1.56 grams, 58%) of white solid after the grinding.
N.M.R(DMSO-d
6)
1Hδ(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)。
Preparation example 4:
4-(6-iodo-4-oxo-4H-quinazoline-3-ylmethyl)-methyl benzoate
Step 1:
4-[(2-amino-5-iodo-benzoylamino)-methyl]-methyl benzoate
In 50 ℃ of solution of the DMF (20 milliliters) of the compound (1.4 grams, 4.84 mmoles) of step 1 gained of preparation example 3, add the hydrochloride (1.17 grams, 5.8 mmoles) of 4-methoxycarbonyl (carbomethoxy)-benzyl amine.Reaction stirring at room 1 hour finds to have the bubble (CO of emerging this moment
2), the TLC demonstration reacts completely.Reaction content is poured into CH is housed
2Cl
2And H
2In the separating funnel of O.After separating, organic layer is with H
2O washs three times to remove DMF, with the salt water washing, and dry (Ha
2SO
4), filtration and vacuum concentration, produce brown solid required acid amides (2.0 grams, quantitatively).
N.M.R(DMSO-d
6)
1Hδ(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-quinazoline-3-ylmethyl)-methyl benzoate
In the triethyl orthoformate solution of the compound of abovementioned steps 1 gained (2.0 grams, 4.84 mmoles), add the TsOH of catalytic amount.Solution refluxed 5 hours, was cooled to room temperature.Vacuum is removed after all volatile matters, and residue uses the flash chromatography purifying, produces the required quinazoline of brown solid.Grind the required compound (1.0 grams, 50%) that the back produces white solid.
N.M.R(CDCl
3)
1Hδ(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)。
Preparation 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-diketone
To 2-amino-5-iodo-Yi Yansuan (18.0 mmole) at H
2In the suspension of O (20 milliliters) and dense HCl (5 milliliters), add diox (50 milliliters), until obtaining settled solution.Drip pure trichloromethylchloroformate (5.95 grams, 30.0 mmoles) (cooling sometimes is not to make the solution boiling), until forming throw out.After the stirring at room 10 minutes, add H
2O (about 100 milliliters) leaches throw out, with a large amount of H
2The O washing.Filter cake vacuum-drying produces required compound.
Step 2:
5-amino-N-(4-fluoro-benzyl)-2-iodo-Isonicotinamide
In the 50 ℃ solution of compound (7.27 mmole) in DMF (20 milliliters) of abovementioned steps 1 gained, drip 4-luorobenzyl amine (9.45 mmole).Reaction stirring at room 10 minutes finds to have the bubble (CO of emerging this moment
2), the TLC demonstration reacts completely.Reaction content is poured into CH is housed
2Cl
2And H
2In the separating funnel of O.After separating, organic layer is with H
2O (3 * 50 milliliters) and salt solution (50 milliliters) washing.Dry (Na
2SO
4), filtration and vacuum concentration, residue is chosen wantonly and use the flash chromatography purifying on silica gel, produces required compound.
Step 3:
3-(4-fluoro-benzyl)-6-iodo-3H-pyrido [3,4-d] pyrimidin-4-one
The tosic acid that in the triethyl orthoformate solution of the compound (7.27 mmole) of abovementioned steps 2 gained, adds catalytic amount.Solution refluxed 5 hours, was cooled to room temperature.Vacuum is removed after all volatile matters, and residue uses the flash chromatography purifying on silica gel, produces required compound.
Preparation example 6:
4-(6-iodo-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl)-methyl benzoate
Step 1
4-{[(5-amino-2-iodo-pyridine-4-carbonyl)-amido]-methyl }-methyl benzoate
In 50 ℃ of solution of the DMF (20 milliliters) of the compound (4.84 mmole) of step 1 gained of preparation example 6, add the hydrochloride (1.17 grams, 5.8 mmoles) of 4-methoxycarbonyl-benzyl amine.To react stirring at room 1 hour, find to have the bubble (CO of emerging this moment
2), the TLC demonstration reacts completely.Reaction content is poured into CH is housed
2Cl
2And H
2In the separating funnel of O.After separating, organic layer is with H
2O washing three times is to remove DMF.Organic layer is with the salt water washing, dry (Na
2SO
4), filtration and vacuum concentration, produce required compound.
Step 2:
4-(6-iodo-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl)-methyl benzoate
In the triethyl orthoformate solution of the compound (4.84 mmole) of abovementioned steps 1 gained, add catalytic amount TsOH.Solution refluxed 5 hours, was cooled to room temperature.Vacuum is removed after all volatile matters, and residue is used the flash chromatography purifying on silica gel, produces required compound.
Preparation example 7:
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid
Step 1:
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylate methyl ester
The compound dissolution that 2.0 gram (5.27 mmole) preparation examples 3 are prepared is in 50 milliliter 1: 1DMF: in the methyl alcohol, add excess of triethylamine and catalytic amount Pd (dppf) Cl
2In.Reaction soln is poured in the autoclave, under the carbon monoxide atmosphere, heated 4 hours under 100 ℃.Reaction is cooled to room temperature and filtration.The filtrate vacuum concentration uses 1: 1 hexane with residue: ethyl acetate purifying, the required product (100%) of generation white solid on silicagel column.
Step 2:
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid
With the compound dissolution of 1.7 gram (5.27 mmole) abovementioned steps 1 preparations in 50 milliliter of 90% tetrahydrofuran (THF): in 10% water.Add 10 Equivalent Hydrogen Lithium Oxide 98mins, reaction soln was refluxed 5 hours.Reaction soln dilutes with 100 ml waters, uses dense this pH value of solution to 1.0 of HCl acidifying.This solution is with 200 milliliters of ethyl acetate extractions, and organic layer is with 2 * 100 ml waters and the washing of 1 * 100 mL of saline.Organic layer is with MgSO
4Dry and concentrated, the required product of generation 1.5 gram pale solids.
Preparation example 8:
3-(4-methylsulfonyl-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid
This compound is to make according to preparation 7 described methods, but uses preparation example 3 prepared compounds in the step 1, wherein uses the 4-luorobenzyl amine in 4-methylsulfonyl-benzyl amine replacement step 2.
Preparation example 9:
3-[4-(tetramethyleneimine-1-alkylsulfonyl)-benzyl]-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid
This compound is to make according to preparation 7 described methods, but uses preparation example 3 prepared compounds in the step 1, wherein uses the 4-luorobenzyl amine in 4-(tetramethyleneimine-1-alkylsulfonyl)-benzyl amine replacement step 2.
Preparation example 10:
4-(6-iodo-4-oxo-4H-quinazoline-3-ylmethyl)-t-butyl perbenzoate
Step 1:
2-amino-5-iodo-benzamide
The compound dissolution that the step 1 of 2.0 gram (6.90 mmole) preparation examples 3 is prepared adds excessive ammonium hydroxide aqueous solution in about 50 milliliters of DMF.After stirring 10 minutes, reaction soln is poured in 100 ml waters, used dense HCl acidifying, use 2 * 100 milliliters of ethyl acetate extractions afterwards.The organic layer that merges is concentrated the required product that produces 1.8 gram (100%) pale powders.
N.M.R(DMSO-d
6)
1Hδ6.68(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-quinazoline-4-one
The compound of 1.8 gram (6.90 mmole) abovementioned steps, 1 gained is suspended in 30 milliliters of triethyl orthoformates.The tosic acid that adds catalytic amount, suspension returning 3 hours.Vacuum is removed all volatile matters, and residue was with 1: 1 methylene fluoride: hexane wash produces the required product of 1.5 gram (80%) pale powders.
MS(APCI)，m/z270.9(M-1)。
N.M.R (DMSO-d
6)
1H δ (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 peak, 1H).
Step 3:
4-(6-iodo-4-oxo-4H-quinazoline-3-ylmethyl)-t-butyl perbenzoate
Restrain (3.31 mmole) abovementioned steps 2 prepared compound dissolutions in 50 milliliters of DMF with 0.9.Add 1.18 gram (3.64 mmole) cesium carbonates and 0.986 gram (3.64 mmole) 4-brooethyl-t-butyl perbenzoate.To react stirring at room 24 hours.Add 200 milliliters of ethyl acetate subsequently, wash with 3 * 100 ml waters then.Organic layer is with MgSO
4Dry and concentrated.Residue is used the methylene dichloride of 4: 1～1: 1 ratio on silicagel column: hexane purifying, the required product of generation 0.97 gram (62%) white powder.
MS(APCI)，m/z?270.9(M-1)。
N.M.R(CDCl
3)
1Hδ(ppm)：5.21(s，2H)，7.36(d，J＝8.5Hz，2H)，7.43(d，J＝8.5Hz，1H)，7.96(dd，J
1＝6.6Hz，J
2＝3.1Hz，2H)，8.01(dd，J
1＝6.5Hz，J
2＝2.1Hz，1H)，8.07(s，1H)，8.64(d，J＝1.8Hz，1H)。
Embodiment 1:
3-(4-methoxyl group-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides
Compound and 2.1 milliliters of (1.85 grams, 12.5 mmoles) triethyl orthoformates of 0.42 gram (1.0 mmole) preparation example 1 were stirred 20 hours at 160 ℃.After the cooling, leach the throw out of gained,, produce the required compound of 1.80 grams (productive rate=42%) from the acetonitrile recrystallization.
TLC：CH
2Cl
2/MeOH?90/10Rf＝0.46
N.M.R(DMSO-d
6)
1Hδ(ppm)：3.75(2s，6H)；4.40(d，2H)；5.115(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：3282，1661，1606，1513，1248，1032，841cm
-1
MP＝169℃
Purity: HPLC=96.7%
Embodiment 2:
3-(4-methoxyl group-benzyl)-2-methyl-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides, hydrochloride
The compound of 0.42 gram (1.0 mmole) preparation example 1, ethanol and 103 microlitres (100 milligrams, the 1 mmole) Acetyl Acetone of 1 milliliter of 6%HCl are stirred, and reflux is spent the night.After the cooling, leach the throw out of gained,, produce required compound from the acetonitrile recrystallization.
TLC：CH
2Cl
2/MeOH90/10Rf＝0.56
N.M.R(DMSO-d
6)
1Hδ(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，1H)；7.80(d，1H)；8.35(d，1H)；8.70(s，1H)；9.35(t，1H)。
IR：3282，1702，1648，1634，1547，1512，1250，1178，1035，793cm
-1。
MP＝208℃
Purity: HPLC=98.9%.
Embodiment 3:
3-(4-methoxyl group-benzyl)-1-methyl-4-oxo-1,2,3,4-tetrahydrochysene-quinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides
In 0.42 gram compound of (1 mmole) preparation example 1 and the stirring solution in 2 ml methanol, add 75 microlitres (1 mmole) formaldehyde.Gained solution refluxed 1 hour.Add 820 microlitre 2M NaOH solution afterwards, keep refluxing 20 minutes.After the cooling, add entry, solution is with ethyl acetate extraction.The decant organic layer, drying, and vacuum concentration.Crude product (0.32 gram, 0.75 mmole) is dissolved in 3 milliliters of dry DMF, under inert atmosphere, stirs.Add 35 milligrams of (0.09 mmole) NaH in this solution, the yellow solution stirring at room of gained 30 minutes adds 55 microlitres (125 milligrams, 0.9 mmole) methyl iodide afterwards.After stirring 30 minutes, reaction mixture is handled according to routine, chromatography on silica gel (methylene dichloride/ether) produces required compound.
N.M.R(DMSO-d
6)
1Hδ(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：1637，1511，1467，1247，1175cm
-1。
MP＝182℃。
Purity: HPLC=95.6%.
Embodiment 4:
3-(4-methoxyl group-benzyl)-1,2,2-trimethylammonium-4-oxo-1,2,3,4-tetrahydrochysene-quinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides
5 milligrams of tosic acid are joined in the stirring solution of compound in 3 milliliters of acetone of 0.42 gram preparation example 1.With the reaction mixture stirred overnight at room temperature.Repeat this process, until reacting completely.With solution for vacuum concentration, crude product methylates by add methyl iodide in the presence of NaH, as described in embodiment 3.After the chromatography purification, products therefrom crystallization in the mixture of methylene dichloride and ether produces required compound.
TLC：CH
2Cl
2/Aceton?90/10Rf＝0.36
N.M.R(DMSO-d
6)
1Hδ(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：1638，1608，1511，1499，1299，1249，1174cm
-1
MP＝168℃
Purity: HPLC=96.4%.
Embodiment 5:
4-[6-(4-methoxyl group-benzyl amido formyl radical)-4-oxo-1,4-dihydro-2H-quinazoline-3-ylmethyl]-phenylformic acid
This compound is according to the described method of the first step of embodiment 3, uses preparation example 2 prepared compounds to make as raw material.
TLC：CH
2Cl
2/MeOH?90/10Rf＝0.10
N.M.R(DMSO-d
6)
1Hδ(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：3314，1678，1629，1513，1294，1248cm
-1
MP＝270℃
Purity: HPLC=97.9%
Embodiment 6:
4-[6-(4-methoxyl group-benzyl amido formyl radical)-1-methyl-4-oxo-1,4-dihydro-2H-quinazoline-3-ylmethyl]-methyl benzoate
This compound is the described method of second step according to embodiment 3, uses embodiment 5 prepared compounds to make as raw material.
TLC：CH
2Cl
2/MeOH?90/10Rf＝0.70
N.M.R(DMSO-d
6)
1Hδ(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：3370，1720，1651，1631，1608，1514，1475，1275，1246，1111cm
-1
MR＝175℃
Purity: HPLC=94.5%
Embodiment 7:
4-[6-(4-methoxyl group-benzyl amido formyl radical)-1-methyl-4-oxo-1,4-dihydro-2H-quinazoline-3-ylmethyl]-methyl benzoate
This compound is according to the described method of the step 2 of preparation example 5, uses embodiment 6 prepared compounds to make as raw material.
TLC：CH
2Cl
2/MeOH?90/10Rf＝0.35
N.M.R(DMSO-d
6)
1Hδ(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：3540，2740，1709，1637，1513，1476，1313，1245，1173cm
-1。
MP＝124℃
Purity: HPLC=95.4%
Embodiment 8:
3-(4-luorobenzyl)-6-(3-phenyl-third-1-alkynyl)-3H-quinazoline-4-one
To (153 milligrams of the compounds of preparation example 3,0.40 mmole) with in the tetrahydrofuran solution of benzyl ethynyl stannane (in-78 ℃ of solution that n-Butyl Lithium joined benzyl acetylene, use tributyltin chloride to stop afterwards and newly make) add the PdCl of catalytic amount
2(Ph
3P)
2And CuI.With the suspension returning that forms 1 hour, and be cooled to room temperature.Filtration and vacuum are removed after the volatile matter, and residue uses the flash chromatography purifying, produce the required compound (80 milligrams, 54%) of white solid.
N.M.R(CDCl
3)
1Hδ(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＝8.3，1.9Hz，1H)，8.08(s，1H)，8.39(d，J＝1.9Hz，1H)；
MS(APCI)，m/z?369.5(M+1)。
Embodiment 9:
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-methyl benzoate
To (165 milligrams of the compounds of preparation example 4,0.39 mmole) with (239 milligrams of benzyl ethynyl stannanes, 0.59 mmole, in-78 ℃ of solution that n-Butyl Lithium joined benzyl acetylene, use tributyltin chloride to stop afterwards and newly make) tetrahydrofuran solution in add the Pd (PPh of catalytic amount
3)
2Cl
2And CuI.With the suspension returning that forms 1 hour.Filtration and vacuum are removed after the volatile matter, and residue is used the flash chromatography purifying, produce the required compound of white solid.
N.M.R(CDCl
3)
1Hδ(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+1)。
Embodiment 10:
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid
Step 1:
4-(6-iodo-4-oxo-4H-quinazoline-3-ylmethyl)-phenylformic acid
To the compound of preparation example 4 (2.25 grams, 5.36 mmoles) at 10%H
2Add lithium hydroxide (2.25 grams, 53.6 mmoles) in the solution in the tetrahydrofuran (THF) of O.To react stirred overnight at room temperature.Use after the dense HCl acidifying, reaction mixture uses ethyl acetate extraction.Organic layer Yi Shui and salt water washing, dry (MgSO
4), filter and vacuum concentration.Crude product uses hexane/ethyl acetate: 4/1 mixture grinds, and produces the required carboxylic acid of 2.00 gram white powders.
N.M.R(DMSO-d
6)
1Hδ(ppm)：5.23(s，2H)，7.40(d，J＝8.3Hx，2H)，7.47(d，J＝8.6Hz，1H)，7.87(d，J＝8.1，2H)，8.1(dd，J
1＝8.6Hz，J
2＝1.9Hx，1H)，8.38(d，J＝1.7Hz，1H)，8.59(s，1H)，12.94(brs，1H)。
MS(APCI)，m/z?404.9(M-1)。
Step 2:
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid
In the solution of compound (0.3 gram, 0.793 mmole) in 6.5 milliliters of DMF of step 1 gained, add diisopropylethylamine (0.381 gram, 2.96 mmoles), CuI (catalytic amount), 3-phenyl-1-propine (0.120 gram, 1.03 mmoles) and Pd (PPh
3)
2Cl
2(catalytic amount).Reaction mixture was 50 ℃ of heating 4 hours.Mixture dilutes with 150 milliliters of ethyl acetate, with 3 * 100 ml waters, the washing of 1 * 100 mL of saline.Organic layer is with MgSO
4Drying, and filter.The filtrate vacuum concentration.Crude product uses hexane/ethyl acetate: 8/1 mixture grinds, and produces the pure required product of 225 milligrams of faint yellow solids.
N.M.R(DMSO-d
6)
1Hδ(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)。
Embodiment 11:
3-(4-luorobenzyl)-6-(3-phenyl-third-1-alkynyl)-3H-pyrido [3,4-d] pyrimidin-4-one
The PdCl that in the tetrahydrofuran solution of the compound (0.40 mmole) of preparation example 5 and benzyl ethynyl stannane (in-78 ℃ of solution that n-Butyl Lithium joined benzyl acetylene, use tributyltin chloride to stop afterwards and newly make), adds catalytic amount
2(Ph
3P)
2And CuI.With the suspension returning that forms 1 hour, and be cooled to room temperature.Filtration and vacuum are removed after the volatile matter, and residue is used the flash chromatography purifying on silica gel, produce required compound.
Embodiment 12:
4-[6-(3-phenyl-third-1-alkynyl)-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl]-methyl benzoate
Compound (0.39 mmole) and (239 milligrams of benzyl ethynyl stannanes to preparation example 6,0.59 mmole, in-78 ℃ of solution that n-Butyl Lithium joined benzyl acetylene, use tributyltin chloride to stop afterwards and newly make) tetrahydrofuran solution in add the PdCl of catalytic amount
2(Ph
3P)
2And CuI.With the suspension returning that forms 1 hour.Filtration and vacuum are removed after the volatile matter, and residue uses the flash chromatography purifying, produces required product.
Embodiment 13:
4-[6-(3-phenyl-third-1-alkynyl)-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl]-phenylformic acid
Step 1:
4-(6-iodo-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl)-phenylformic acid
To the compound (5.36 mmole) of preparation example 6 at 10%H
2Add lithium hydroxide (2.25 grams, 53.6 mmoles) in the solution of the tetrahydrofuran (THF) of O.The reaction stirred overnight at room temperature.Use after the dense HCl acidifying, reaction mixture uses ethyl acetate extraction.Organic layer Yi Shui and salt water washing, dry (MgSO
4), filter and vacuum concentration.Crude product uses hexane/ethyl acetate: 4/1 grinds, and produces required compound.
Step 2:
4-(6-(3-phenyl-third-1-alkynyl)-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl)-phenylformic acid
Compound (0.793 mmole) to step 1 gained adds diisopropylethylamine (0.381 gram, 2.96 mmoles), CuI (catalytic amount), 3-phenyl-1-propine (0.120 gram, 1.03 mmoles) and Pd (PPh in the solution of 6.5 milliliters of DMF
3)
2Cl
2(catalytic amount).Reaction mixture is warm 4 hours at 50 ℃.Then mixture is diluted with 150 milliliters of ethyl acetate, with 3 * 100 ml waters, the washing of 1 * 100 mL of saline.Organic layer is with MgSO
4Drying, and filter.The filtrate vacuum concentration.Crude product uses hexane/ethyl acetate: 8/1 grinds, and produces required compound.
Embodiment 14:
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 3-methoxyl group-benzyl acid amides
Restrain (0.671 mmole) preparation example 7 prepared compound dissolutions in 50 milliliters of chloroforms with 0.2.Add 110 milligrams of 3-methoxy-benzyl amine, 205 milligrams of Mukaiyama reagent and 163 milligrams of triethylamines.The reaction soln stirred overnight at room temperature.Reaction soln uses 1: 1 hexane through concentrating on silicagel column: ethyl acetate purifying, the required product of 150 milligrams of pale solids of generation.
N.M.R(CDCl
3)
1Hδ(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＝2.0Hz，1H)。
Embodiment 15:
3-(4-methylsulfonyl-benzyl-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides
This compound is according to embodiment 14 described methods, uses as the preparation example 8 prepared compounds of raw material and 4-methoxy-benzyl amine to make.
MS(APCI)，m/z?478.1(M+1)。
N.M.R(DMSO-d
6)
1Hδ(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＝8.7Hz，1H)，8.51(s，1H)，9.15(s，1H)。
Embodiment 16:
4-oxo-3-[4-(tetramethyleneimine-1-alkylsulfonyl)-benzyl]-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides
This compound is according to embodiment 14 described methods, uses as the preparation example 9 prepared compounds of raw material and 4-methoxy-benzyl amine to make.
MS(APCI)，m/z?533.2(M+1)。
N.M.R(DMSO-d
6)
1Hδ(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＝8.0Hz，2H)，7.25(s，1H)，7.54(d，J＝8.1Hz，2H)，7.74(d，J＝8.1Hz，2H)，8.26(d，J＝8.3Hz，1H)，8.64(s，1H)，8.66(s，1H)，9.27(s，1H)。
Embodiment 17:
4-[6-(3-methoxyl group-benzyl amido formyl radical)-4-oxo-4H-quinazoline-3-ylmethyl]-phenylformic acid
Required product is that the method according to embodiment 14 makes, and not existing together is to replace 4-luorobenzyl amine in the step 2 of preparation example 3 with 3-aminomethyl-t-butyl perbenzoate, last, at room temperature stirs collected residue 30 minutes in excessive trifluoroacetic acid.After the vacuum-evaporation volatile matter, leach residue, to obtain the required product of the solid shape of canescence.
N.M.R(DMSO-d
6)
1Hδ(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)。
Embodiment 18:
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl] phenylformic acid
Step 1:
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-t-butyl perbenzoate
Restrain the compound dissolution of (6.48 mmole) preparation examples 10 in 50 milliliters of DMF with 3.0.Pd (the PPh that thereupon adds cupric iodide (I), 3.01 gram (25.9 mmole) 3-phenyl-1-propine and the catalytic amount of 3.34 gram (25.9 mmole) diisopropylethylamine, catalytic amount in regular turn
3)
2Cl
2Reaction soln was stirred 24 hours down at 50 ℃, with 300 milliliters of ethyl acetate dilutions, and with 3 * 200 surprised ml waters, the washing of 1 * 200 mL of saline.Organic layer is with MgSO
4Dry and concentrated.Residue is used 4: 1 hexanes on silicagel column: ethyl acetate is cumulative to 1: 1 hexane: ethyl acetate purifying, the required product of generation waxy substance.
N.M.R(DMSO-d
6)
1Hδ(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-third-1-alkynyl)-4H-quinazoline-3-ylmethyl] phenylformic acid
Excessive (20 milliliters) trifluoroacetic acid is joined in the compound of abovementioned steps 1 gained.After stirring 30 minutes, remove all volatile matters, with residue with 1: 1 hexane: ethyl acetate is ground.The collecting precipitation thing with the small amount of methanol washing, produces the required product of 1.82 gram pale solids after filtration.
N.M.R (DMSO-d
6)
1H δ (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 (broad peak s, 1H), 8.09 (d, J=1.6Hz, 1H), 8.58 (s, 1H).
Embodiment 19:
4-{6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid
This product is that the method according to embodiment 18 makes, and unique difference is that employed 3-phenyl in the step 1-1-propine substitutes with 1-methoxyl group-4-Propargyl-benzene.Obtain the product of the solid shape of white.
N.M.R (DMSO-d
6)
1H δ (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, 2H), 7.81 (dd, J
1=8.3Hz, J
2=1.5Hz, 1H), 7.88 (d, J=8.1Hz, 2H), 8.08 (d, J=1.5Hz, 1H), 8.58 (s, 1H), 12.94 (broad peak s, 1H).
Embodiment 20:
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzamide
The compound of 0.1 gram (0.245 mmole) embodiment 18 is suspended in 50 milliliters of methylene dichloride.Add 3.54 milligrams of oxalyl chlorides (0.279 mmole), add 1 DMF afterwards.To be reflected at refluxed under nitrogen 2 hours, again stirring at room 12 hours.Add excessive 0.5M ammonia De dioxane solution.To react stirring at room 1 hour.Vacuum is removed solvent, and with 1: 1 water: methanol wash produced 70 milligrams of required products of canescence powdered.
MS(APCI)，m/z?394.1(M+1)。
N.M.R(DMSO-d
6)
1Hδ(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)。
Embodiment 21:
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid (2-methoxyl group-pyridin-4-yl methyl)-acid amides
Preparation example 7 prepared compounds (227 milligrams, 0.76 mmole), 2-methoxyl group-pyridin-4-yl-methylamine (138 milligrams, 1.0 mmoles) and Mukaiyama reagent (256 milligrams, 1.0 mmoles) are dissolved in CHCl
3In (10 milliliters), add Et
3N (1 milliliter, excessive).The solution that forms was refluxed 3 hours, be cooled to room temperature.Solution is through the flash chromatography purifying, produces 34 milligrams of the required products of white solid, 63%.
MS(APCI)，m/z?419.2(M+1)。
N.M.R(DMSO-d
6)
1Hδ(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)。
Embodiment 22:
3-[(3,5-two fluoro-4-hydroxyls)-benzyl]-6-(3-phenyl-third-1-alkynyl)-3H-quinazoline-4-one
To 3-[(3,5-two fluoro-4-hydroxyls)-benzyl]-6-iodo-3H-quinazoline-4-one is (according to the method for preparation example 3, but use (3 in the step 2,5-two fluoro-4-hydroxyls)-benzyl amine (0.3 gram, 720 mmoles) make) add diisopropylethylamine (0.381 gram in the solution in 6.5 milliliters of DMF, 2.96 mmole), 3-phenyl-1-propine (0.34 gram, 2.9 mmoles), CuI (catalytic amount) and Pd (PPh
3)
2Cl
2(catalytic amount).Reaction mixture was heated 4 hours at 50 ℃.Mixture is diluted with 150 milliliters of ethyl acetate, with 3 * 100 ml waters, the washing of 1 * 100 mL of saline.Organic layer is with MgSO
4Drying and filtration.The filtrate vacuum concentration.Crude product produces the required product of 225 milligrams of pure faint yellow solids through the flash chromatography purifying.
MS(APCI)，m/z?403.1(M+1)。
N.M.R(DMSO-d
6)
1Hδ(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)。
Embodiment 23:
3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 3-methoxyl group-benzyl acid amides
Step 1:
6-chloro-3-(3-fluoro-benzyl)-3H-pyrido [3,4-d] pyrimidin-4-one
Initial substance 6-chloro-3H-pyrido [3,4-d] pyrimidin-4-one (710 milligrams, 3.92 mmoles, according to J.Chem.Soc., Perkin Trans.1996,1,2221 method preparation) be dissolved among the DMF (20 milliliters).Add Cs in regular turn
2CO
3(1.66 grams, 5.1 mmoles) and 3-fluorobenzyl chloride (737 milligrams, 5.1 mmoles).The reaction stirred overnight at room temperature is poured in the water.Use CH
2Cl
2After the extraction, with organic layer with H
2O and salt water washing, dry (Na
2SO
4) and filter.Remove after the solvent, residue produces the product of white solid through the flash chromatography purifying.
MS(APCI)，m/z?290.0(M+1)。
N.M.R(CDCl
3)
1Hδ(ppm)：8.92(s，1H)，8.10(d，J＝9.6Hz，2H)，7.0-7.4(s，5H)，5.17(m，2H)。
Step 2:
3-(3-luorobenzyl)-4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylate methyl ester
With Pd (dppf) Cl of abovementioned steps 1 prepared compound (3.0 grams, 1.07 mmoles) with excess of triethylamine and catalytic amount
2Be dissolved in together in 50 ml methanol.Reaction soln is poured in the autoclave, is heating 4 hours under the carbon monoxide atmosphere under 100 ℃.Reaction is cooled to room temperature and filters.Filtrate vacuum concentration, residue use 1: 1 hexane on silicagel column: ethyl acetate purifying, the required product (100%) of generation white solid.
MS(APCI)，m/z?314.0(M+1)。
N.M.R(CDCl
3)
1Hδ(ppm)：9.24(s，1H)，8.95(sm，12H)，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-methoxyl group-benzyl acid amides
To 3-methoxy-benzyl amine (144 milligrams, 1.05 mmoles) at CH
2Cl
2In 0 ℃ of solution in add AlMe
3(0.52 milliliter, 1.05 mmoles).Reaction stirring at room 2 hours.Add abovementioned steps 2 prepared compounds (111 milligrams, 0.35 mmole) afterwards at CH
2Cl
2In solution, and the reaction stirring at room that will form 2 hours is poured in the water.Use CH
2Cl
2After the extraction, organic layer is with H
2O and salt water washing, dry (Na
2SO
4) and filter.Remove after the solvent, residue produces the product of white solid through the flash chromatography purifying.
MS(APCI)，m/z?419.1(M+1)。
N.M.R(CDCl
3)
1Hδ(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＝6.6Hz，1H)，3.67(s，3H)。
Embodiment 24:
3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 4-methoxyl group-benzyl acid amides
This compound is to use 4-methoxy-benzyl amine to make in step 3 according to the method for embodiment 23.
MS(APCI)，m/z?419.1(M+1)。
N.M.R(CDCl
3)
1Hδ(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)。
Embodiment 25:
4-[4-oxo-6-(3-phenyl-the third-1,2-dialkylene)-4H-quinazoline-3-ylmethyl]-phenylformic acid
With 0.105 gram (0.257 mmole) embodiment 9 compound dissolutions in 25 milliliter of 90% tetrahydrofuran (THF): in 10% water.Add 10 Equivalent Hydrogen Lithium Oxide 98mins.Reaction soln was refluxed 3 hours, add 200 milliliters of ethyl acetate, use dense HCl acidifying, this solution is with 2 * 200 ml waters and the washing of 1 * 100 mL of saline.Organic layer is with MgSO
4Dry and concentrated.Residue uses 95% ethyl acetate on silicagel column: 5%MeOH purifying, the product of 30 milligrams of pale yellow powders of generation.
MS(APCI)，m/z?481.2(M+1)
N.M.R(DMSO-d
6)
1Hδ(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＝1.7Hz，1H)，7.87(d，J＝8.1Hz，2H)，8.07(s，1H)，8.53(s，1H)。
Embodiment 26 to 71:
These compounds are according to preparation example 5 and embodiment 8 described methods, use corresponding material and reagent to make.
(26.4-{6-[3-4-methoxyl group-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(27.3-4-methylsulfonyl-benzyl)-6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
(28.4-{6-[3-3-methoxyl group-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(29.3-4-methylsulfonyl-benzyl)-6-[3-(3-methoxyl group-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
30.4-[4-oxo-6-(3-pyridin-4-yl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid
(31.3-4-methylsulfonyl-benzyl)-6-(3-pyridin-4-yl-third-1-alkynyl)-3H-quinazoline-4-one,
32.4-[4-oxo-6-(3-pyridin-3-yl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid
(33.3-4-methylsulfonyl-benzyl)-6-(3-pyridin-3-yl-third-1-alkynyl)-3H-quinazoline-4-one,
(34.4-{6-[3-4-fluoro-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(35.6-[3-4-fluoro-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-quinazoline-4-one,
(36.4-{6-[3-3-fluoro-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(37.6-[3-3-fluoro-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-quinazoline-4-one,
(38.4-{6-[3-4-chloro-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(39.6-[3-4-chloro-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-quinazoline-4-one,
(40.4-{6-[3-3-chloro-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(41.6-[3-3-chloro-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-quinazoline-4-one,
(42.4-{6-[3-4-bromo-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(43.6-[3-4-bromo-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-quinazoline-4-one,
(44.4-{6-[3-3-bromo-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(45.6-[3-3-bromo-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-quinazoline-4-one,
(46.4-{6-[3-4-nitro-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(47.3-4-methylsulfonyl-benzyl)-6-[3-(4-nitro-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
(48.4-{6-[3-2-methoxyl group-pyridin-4-yl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(49.3-4-methylsulfonyl-benzyl)-6-[3-(2-methoxyl group-pyridin-4-yl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
(50.4-{6-[3-4-methyl sulfenyl-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(51.3-4-methylsulfonyl-benzyl)-6-[3-(4-methyl sulfenyl-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
(52.4-{6-[3-3-methyl sulfenyl-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
(53.3-4-methylsulfonyl-benzyl)-6-[3-(3-methyl sulfenyl-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
54.4-[4-oxo-6-(3-p-methylphenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid,
55.3-[4-methylsulfonyl-benzyl)-6-(3-p-methylphenyl-third-1-alkynyl)-3H-quinazoline-4-one,
56.4-[4-oxo-6-(tolyl between 3--third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid,
57.3-[4-methylsulfonyl-benzyl)-6-(tolyl between 3--third-1-alkynyl)-3H-quinazoline-4-one,
(58.4-[6-3-imidazoles-1-base-third-1-alkynyl)-4-oxo-4H-quinazoline-3-ylmethyl]-phenylformic acid,
59.4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzsulfamide,
60.4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzonitrile,
(61.3-3-chloro-benzyl)-6-(4-phenyl-Ding-1-alkynyl)-3H-quinazoline-4-one,
(62.3-3-chloro-benzyl)-6-(3-phenyl-Ding-1-alkynyl)-3H-quinazoline-4-one,
63.4-[4-oxo-6-(3-pyrazol-1-yl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid,
(64.6-3-phenyl-third-1-alkynyl)-3-[4-(1H-tetrazolium-5-yl)-benzyl]-the 3H-quinazoline-4-one,
(65.3-3,4-two fluoro-benzyls)-6-[3-(pyridin-4-yl oxygen)-third-1-alkynyl]-the 3H-quinazoline-4-one,
(66.3-3,4-two fluoro-benzyls)-6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
67.N-{4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenyl }-ethanamide,
(68.3-3,4-two fluoro-benzyls)-6-(3-phenyl-third-1-alkynyl]-the 3H-quinazoline-4-one,
(69.3-4-ethanoyl-benzyl)-6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
(70.6-3-phenyl-third-1-alkynyl)-3-pyridin-4-yl methyl-3H-quinazoline-4-one,
(71.6-[3-4-methoxyl group-phenyl)-third-1-alkynyl]-3-pyridin-4-yl methyl-3H-quinazoline-4-one,
Embodiment 72 to 103:
These compounds are the methods according to record among preparation example 6 and the embodiment 11, use corresponding material and reagent to make.
(72.4-{6-[3-4-methoxyl group-phenyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(73.3-4-methylsulfonyl-benzyl)-6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-3H-pyrido [3,4-d] pyrimidin-4-one,
(74.4-{6-[3-3-methoxyl group-phenyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(75.3-4-methylsulfonyl-benzyl)-6-[3-(3-methoxyl group-phenyl)-third-1-alkynyl]-3H-pyrido [3,4-d] pyrimidin-4-one,
76.4-[4-oxo-6-(3-pyridin-4-yl-third-1-alkynyl)-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(77.3-4-methylsulfonyl-benzyl)-6-(3-pyridin-4-yl-third-1-alkynyl)-3H-pyrido [3,4-d] pyrimidin-4-one,
78.4-[4-oxo-6-(3-pyridin-3-yl-third-1-alkynyl)-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(79.3-4-methylsulfonyl-benzyl)-6-(3-pyridin-3-yl-third-1-alkynyl)-3H-pyrido [3,4-d] pyrimidin-4-one,
(80.4-{6-[3-4-fluoro-phenyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(81.6-[3-4-fluoro-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-pyrido [3,4-d] pyrimidin-4-one
(82.4-{6-[3-3-fluoro-phenyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(83.6-[3-3-fluoro-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-pyrido [3,4-d] pyrimidin-4-one
(84.4-{6-[3-4-chloro-phenyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(85.6-[3-4-chloro-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-pyrido [3,4-d] pyrimidin-4-one
(86.4-{6-[3-3-chloro-phenyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(87.6-[3-3-chloro-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-pyrido [3,4-d] pyrimidin-4-one
(88.4-{6-[3-4-bromo-phenyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(89.6-[3-4-bromo-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-pyrido [3,4-d] pyrimidin-4-one
(90.4-{6-[3-3-bromo-phenyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(91.6-[3-3-bromo-phenyl)-third-1-alkynyl]-3-(4-methylsulfonyl-benzyl)-3H-pyrido [3,4-d] pyrimidin-4-one
(92.4-{6-[3-4-nitro-phenyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(93.3-4-methylsulfonyl-benzyl)-6-[3-(4-nitro-phenyl)-third-1-alkynyl]-3H-pyrido [3,4-d] pyrimidin-4-one,
(94.4-{6-[3-2-methoxyl group-pyridin-4-yl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(95.3-4-methylsulfonyl-benzyl)-6-[3-(2-methoxyl group-pyridin-4-yl)-third-1-alkynyl]-3H-pyrido [3,4-d] pyrimidin-4-one,
(96.4-{6-[3-4-methyl sulfenyl-benzyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(97.3-4-methylsulfonyl-benzyl)-6-[3-(4-methyl sulfenyl-phenyl)-third-1-alkynyl]-3H-pyrido [3,4-d] pyrimidin-4-one,
(98.4-{6-[3-3-methyl sulfenyl-benzyl)-third-1-alkynyl]-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(99.3-4-methylsulfonyl-benzyl)-6-[3-(3-methyl sulfenyl-phenyl)-third-1-alkynyl]-3H-pyrido [3,4-d] pyrimidin-4-one,
100.4-[4-oxo-6-(3-p-methylphenyl-third-1-alkynyl)-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
(101.3-4-methylsulfonyl-benzyl)-6-(3-p-methylphenyl-third-1-alkynyl)-3H-pyrido [3,4-d] pyrimidin-4-one,
102.4-[4-oxo-6-(tolyl between 3--third-1-alkynyl)-4H-pyrido [3,4-d] pyrimidin-3-yl methyl }-phenylformic acid,
103. and 3-(4-methylsulfonyl-benzyl)-6-(tolyl between 3--third-1-alkynyl)-3H-pyrido [3,4-d] pyrimidin-4-one.
Embodiment 104 and 105
These compounds are according to embodiment 14 and 21 described methods, use corresponding material and reagent to make.
(104.3-3,4-two fluoro-phenyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid (2-methoxyl group-pyridin-4-yl methyl)-acid amides,
(105.3-3,4-two fluoro-phenyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides.
The pharmaceutical research of The compounds of this invention
Embodiment 106: the evaluation of the external activity of MMP-13 inhibitor compound of the present invention
General formula of the present invention (I) compound is by suppressing MMP-13 by the test The compounds of this invention ability of the proteolysis of peptide substrates to be estimated to the inhibition activity of matrix metalloproteinase-13.Employed peptide substrates is following peptide: Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt in the test.
The inhibition activity of general formula of the present invention (I) compound is with IC
50Value representation, it is the inhibitor concentration of the matrix metal proteinase activity 50% of inhibition research.When carrying out this test, prepare the reaction medium of 100 microlitre volumes, it contains: 50mM HEPES damping fluid, 10mM CaCl
2And 1mM 5,5 '-dithiobis-(2-nitrobenzoic acid) (DTNB) and the substrate of 100 μ M, and pH transfers to 7.0.
The 2.0%DMSO solution of cumulative concentration inhibition compound and the people MMP-13 catalysis position of 2.5nM are joined in the sample.Contained inhibitor concentration is 100 μ M to 0.5nM in the sample.The enzymolysis of peptide substrate is measured and is used the spectrograph that reads microtiter plate, under laboratory temperature, measures absorbancy and detect under 405 nanometers, and this measurement was carried out 10 to 15 minutes continuously.This IC
50Value draws from curve calculation, wherein with respect to the catalytic activity percentages show of control group at the X-axle, and inhibitor concentration is presented at the Y-axle.
The compound of embodiment 1 to 10,14 to 19,21,23 to 25,58 to 60,62,64 to 71,104,105 is to the IC of MMP-13
50Value all is lower than 1 μ M.
The test of aforementioned inhibition MMP-13 improves and is used to measure the ability of general formula (I) compound inhibition matrix metalloproteinase MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 and MMP-14.The gained result shows the IC of The compounds of this invention to MMP-13
50Value has the IC of about more same compound to other test matrix metalloproteases usually
50Low about 100 times of value.
Claims (33)
1. compound with general formula (I):
Wherein:
● X
1, X
2And X
3Represent nitrogen-atoms or group-CR independently of one another
3, R wherein
3Expression is selected from hydrogen, (C
1-C
6) alkyl, amino, list (C
1-C
6) alkyl amine group, two (C
1-C
6) alkyl amine group, hydroxyl, (C
1-C
6) group of alkoxyl group and halogen,
Condition is a radicals X
1, X
2And X
3In at the most two represent nitrogen-atoms simultaneously,
● G
1Expression is selected from general formula (i/a) and group (i/b):
Wherein:
Group N-R in the carbon atom of-numbering 2 and the ring
1Link to each other,
-R
4And R
5Identical or different independently of one another, and expression is selected from hydrogen, (C
1-C
6) alkyl, aryl, aryl (C
1-C
6) alkyl, cycloalkyl, cycloalkyl (C
1-C
6) alkyl, heteroaryl, heteroaryl (C
1-C
6) alkyl, Heterocyclylalkyl and Heterocyclylalkyl (C
1-C
6) group of alkyl,
-R
6Expression is selected from following group:
√ hydrogen, trifluoromethyl, OR
7, NR
7R
8, R wherein
7And R
8Identical or different independently of one another, and expression hydrogen or (C
1-C
6) alkyl,
√ (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (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, Heterocyclylalkyl and Heterocyclylalkyl (C
1-C
6) alkyl, these groups are optional to be replaced through one or more group, and described group can be identical or different independently of one another, and be selected from halogen, amino, list (C
1-C
6) alkyl amine group, two identical or different independently of one another (C of each moieties
1-C
6) alkyl amine group, cyano group, three halo (C
1-C
6) alkyl, (C
1-C
6) acyl group ,-C (=O) OR
7,-OR
7And-SR
7, R wherein
7As above definition,
● G
2Be be selected from carbon-to-carbon triple bond ,-CH=C=CH-, C=O, C=S, S (O)
N1Group, wherein n1 represents by 0 to 2 and comprises 0 and 2 integer, and the group of general formula (i/c):
Wherein number 1 carbon atom and connect the dicyclo of general formula (I) compound, Y
1Expression be selected from oxygen, sulphur ,-NH and-N (C
1-C
6) group of alkyl, and Y
2Be be selected from oxygen, sulphur ,-NH and-N (C
1-C
6) group of alkyl,
● n represents by 0 to 6 and comprises 0 and 6 integer,
● Z
1Expression-CR
9R
10, R wherein
9And R
10Identical or different independently of one another, and expression is selected from hydrogen, (C
1-C
6) alkyl, three halo (C
1-C
6) alkyl, halogen ,-OR
7,-SR
7And-C (=O) OR
7, R wherein
7As preamble definition, amido, list (C
1-C
6) alkyl amine group, two identical or different (C of each moieties wherein
1-C
6) group of alkyl amine group, and
-wherein when n more than or equal to 2 the time, hydrocarbon chain Z
1Optional one or two independence or the conjugated multikey of containing,
-and/or wherein when n more than or equal to 2 the time ,-CR
9R
10One of can choose wantonly by being selected from oxygen, the S (O) of n1 such as preamble definition wherein
N1,-NH reaches-N (C
1-C
6) group of alkyl replaces,
● A represents to be selected from the group of aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl, and these groups are 5-or 6-person's monocycle or the dicyclo be made up of two 5-or 6-person's monocycle,
● R
1Expression is selected from following group:
-hydrogen,
-(C
1-C
6) alkyl, (C
1-C
6) thiazolinyl, (C
1-C
6) alkynyl, these groups can be chosen wantonly through one or more group and replace, and described substituting group can be identical or different independently of one another, and be selected from amido, cyano group, three halo (C
1-C
6) alkyl, cycloalkyl ,-C (=O) NR
7R
8,-C (=O) OR
8, OR
8, SR
8Group, R wherein
7And R
8Can be identical or different independently of one another, and expression hydrogen or (C
1-C
6) alkyl,
-and the group of general formula (i/d):
√ wherein p for by 0 to 8 and comprise 0 and 8 integer,
√ Z
2Expression-CR
11R
12, R wherein
11And R
12Identical or different independently of one another, and expression is selected from hydrogen, (C
1-C
6) alkyl, phenyl, three halo (C
1-C
6) alkyl, halogen, amino, OR
7, SR
7And-C (=O) OR
7Group, R wherein
7Expression hydrogen or (C
1-C
6) alkyl, and
-wherein when p more than or equal to 2 the time, hydrocarbon chain Z
2Optional one or two independence or the conjugated multikey of containing,
-and/or wherein when n more than or equal to 2 the time ,-CR
11R
12One of can choose wantonly by being selected from oxygen, the S (O) of n1 such as preamble definition wherein
N1,-NH ,-N (C
1-C
6) group of alkyl and carbonyl replaces,
√ B represents to be selected from the group of aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl, and these groups are 5-or 6-person's monocycle or the dicyclo be made up of two 5-or 6-person's monocycle,
√ q is for by 0 to 7 and comprise 0 and 7 integer,
The √ group G
3Identical or different independently of one another, and be selected from (C
1-C
6) alkyl, halogen, CN, NO
2, CF
3, OCF
3,-(CH
2)
kNR
13R
14,-N (R
13) C (=O) R
14,-N (R
13) C (=O) OR
14,-N (R
13) SO
2R
14,-N (SO
2R
13)
2,-OR
13,-S (O)
K1R
13,-SO
2-N (R
13)-(CH
2)
K2-NR
14R
15,-(CH
2)
kSO
2NR
13R
14,-X
4(CH
2)
kC (=O) OR
13,-(CH
2)
kC (=O) OR
13,-C (=O) O-(CH
2)
K2-NR
13R
14,-C (=O) O-(CH
2)
K2-C (=O) OR
16,-X
4(CH
2)
kC (=O) NR
13R
14,-(CH
2)
kC (=O) NR
13R
14,-R
17-C (=O) OR
13,-X
5-R
18And-C (=O)-R
19-NR
13R
14, wherein:
-X
4Expression is selected from Sauerstoffatom, optional by one or two sulphur atom that Sauerstoffatom replaced, by hydrogen atom or (C
1-C
6) group of the nitrogen-atoms that alkyl replaced,
-k is for by 0 to 3 and comprise 0 and 3 integer,
-k1 is for by 0 to 2 and comprise 0 and 2 integer,
-k2 is for by 1 to 4 and comprise 1 and 4 integer,
-R
13, R
14And R
15Identical or different independently of one another, and be selected from hydrogen and (C
1-C
6) alkyl,
-R
16Expression is selected from (C
1-C
6) alkyl ,-R
19-NR
13R
14,-R
19-NR
13-C (=O)-R
19-NR
14R
15And-C (=O) O-R
19-NR
13R
14Group, R wherein
19Expression straight or branched (C
1-C
6) alkylidene group, and R
13, R
14And R
15As the preamble definition,
-R
17Expression (C
3-C
6) cycloalkyl,
-X
5The expression be selected from singly-bound ,-CH
2-, Sauerstoffatom, optional through one or two sulphur atom that Sauerstoffatom replaced and through hydrogen atom or (C
1-C
6) group of the nitrogen-atoms that alkyl replaced,
-R
18Expression is selected from following group:
O5 or 6-person's monocyclic aryl, heteroaryl, it is chosen wantonly and replaces through one or more group, and described substituting group can be identical or different, and be selected from (C
1-C
6) alkyl, halogen, hydroxyl, cyano group, tetrazyl, amino and-C (=O) OR
7, R wherein
7Expression hydrogen or (C
1-C
6) alkyl,
O5-or 6-person's monocyclic cycloalkyl, Heterocyclylalkyl, it is chosen wantonly and replaces through one or more group, and described substituting group can be identical or different, and be selected from (C
1-C
6) alkyl, halogen, hydroxyl, oxo, cyano group, tetrazyl, amino and-C (=O) OR
7, R wherein
7Expression hydrogen or (C
1-C
6) alkyl,
● m is for by 0 to 7 and comprise 0 and 7 integer,
● radicals R
2Identical or different independently of one another, and be selected from (C
1-C
6) alkyl, halogen ,-CN, NO
2, SCF
3,-CF
3,-OCF
3,-NR
7R
8,-OR
8,-SR
8,-SOR
8,-SO
2R
8,-(CH
2)
kSO
2NR
7R
8,-X
7(CH
2)
kC (=O) OR
8,-(CH
2)
kC (=O) OR
8,-X
7(CH
2)
kC (=) NR
7R
8,-(CH
2)
kC (=) NR
7R
8And-X
8-R
20Wherein:
-X
7Expression is selected from oxygen, optional through one or two sulphur that Sauerstoffatom replaced and through hydrogen or (C
1-C
6) group of the nitrogen that alkyl replaced,
-k is 0 to 3 and comprises 0 and 3 integer,
-R
7And R
8Identical or different independently of one another, and be selected from hydrogen and (C
1-C
6) alkyl,
-X
8The expression be selected from singly-bound ,-CH
2, Sauerstoffatom, optional through one or two sulphur atom that Sauerstoffatom replaced and through hydrogen atom or (C
1-C
6) group of the nitrogen-atoms that alkyl replaced,
-R
20Expression 5-or 6-person's monocyclic aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl, it is chosen wantonly and replaces through one or more group, and described substituting group can be identical or different, and be selected from (C
1-C
6) alkyl, halogen, hydroxyl and amino, and when this ring during for heterocycle, it comprises 1 to 4 heteroatoms that is selected from nitrogen, oxygen and sulphur,
Randomly, its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof,
When specification sheets is not put down in writing, be construed as:
-aryl represents to contain the aromatic monocyclic or the bicyclic system of 5 to 10 carbon atoms, and under the situation that is bicyclic system, then wherein a ring has an aromaticity, another ring can be aromaticity or by partial hydrogenation,
-heteroaryl is represented aforementioned aryl, and wherein 1 to 4 carbon atom is replaced by 1 to 4 heteroatoms that is selected from oxygen, sulphur and nitrogen,
-cycloalkyl represents to contain the monocycle or the bicyclic system of 3 to 10 carbon atoms, this system be saturated or part undersaturated, but do not have aromaticity,
-and Heterocyclylalkyl represent aforementioned cycloalkyl, wherein 1 to 4 carbon atom is replaced by 1 to 4 heteroatoms that is selected from oxygen, sulphur and nitrogen.
2. compound as claimed in claim 1, wherein:
● G
2Expression is selected from C=O, C=S, S (O)
N1Group, wherein n1 represents by 0 to 2 and comprises 0 and 2 integer, or the group of following formula (i/c):
Wherein numbering 1 carbon atom is the dicyclo that connects the compound of general formula (I), Y
1Expression be selected from oxygen, sulphur ,-NH and-N (C
1-C
6) group of alkyl, and Y
2Expression be selected from oxygen, sulphur ,-NH and-N (C
1-C
6) group of alkyl,
● X
1, X
2, X
3, G
1, n, Z
1, A, R
1, m and R
2As definition, randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof in the general formula (I).
3. compound as claimed in claim 1, wherein:
● G
2The expression carbon-to-carbon triple bond,
● n represents by 1 to 6 and comprises 1 and 6 integer,
● X
1, X
2, X
3, G
1, Z
1, A, R
1, m and R
2As definition, randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof in the general formula (I).
4. compound as claimed in claim 1, wherein:
● G
2The expression carbon-to-carbon triple bond,
● n is 0,
● Z
1Do not exist,
● A represents to be selected from the group of heteroaryl, cycloalkyl, Heterocyclylalkyl, and these groups are 5-or 6-person's monocycle or the dicyclo be made up of two 5-or 6-person's monocycle,
● X
1, X
2, X
3, G
1, R
1, m and R
2As definition in the general formula (I),
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
5. compound as claimed in claim 1, wherein:
● G
2The expression carbon-to-carbon triple bond,
● n is 0,
● Z
1Do not exist,
● A represents phenyl,
● R
1The group of expression hydrogen atom or general formula (i/d):
√ wherein p for by 0 to 8 and comprise 0 and 8 integer,
√ Z
2Expression-CR
11R
12, R wherein
11And R
12Identical or different independently of one another, and expression is selected from hydrogen, (C
1-C
6) alkyl, phenyl, three halo (C
1-C
6) alkyl, halogen, amino, OR
7, SR
7And-C (=O) OR
7Group, R wherein
7Expression hydrogen or (C
1-C
6) alkyl, and
-wherein when p more than or equal to 2 the time, hydrocarbon chain Z
2Optional one or two independence or the conjugated multikey of containing,
-and/or wherein when n more than or equal to 2 the time ,-CR
11R
12One of can choose wantonly by being selected from oxygen, the S (O) of n1 such as preamble definition wherein
N1,-NH ,-N (C
1-C
6) group of alkyl and carbonyl replaces,
√ B represents phenyl,
√ q is for by 1 to 7 and comprise 1 to 7 integer,
The √ group G
3Can be identical or different, and be selected from-(CH
2)
kNR
13R
14,-N (R
13) C (=O) OR
14,-N (R
13) SO
2R
14,-N (SO
2R
13)
2,-S (O)
kR
13,-SO
2-N (R
13)-(CH
2)
K2-NR
14R
15,-(CH
2)
kSO
2NR
13R
14,-X
4(CH
2)
kC (=O) OR
13,-(CH
2)
kC (=O) OR
13,-C (=O) O-(CH
2)
K2-NR
13R
14,-C (=O) O-(CH
2)
K2-C (=O) OR
16,-X
4(CH
2)
kC (=O) NR
13R
14,-(CH
2)
kC (=O) NR
13R
14,-R
17-C (=O) OR
13,-X
5-R
18,-C (=O)-R
19-NR
13R
14And-X
6-R
21Wherein:
-X
4Expression is selected from Sauerstoffatom, optional through one or two sulphur atom that Sauerstoffatom replaced, through hydrogen atom or (C
1-C
6) group of the nitrogen-atoms that alkyl replaced,
-k is for by 0 to 3 and comprise 0 and 3 integer,
-k1 is for by 1 to 2 and comprise 1 and 2 integer,
-k2 is for by 1 to 4 and comprise 1 and 4 integer,
-R
13, R
14And R
15Identical or different independently of one another, and be selected from hydrogen and (C
1-C
6) alkyl,
-R
16Expression is selected from (C
1-C
6) alkyl ,-R
19-NR
13R
14,-R
19-NR
13-C (=O)-R
19-NR
14R
15And-C (=O) O-R
19-NR
13R
14Group, R wherein
19Expression straight or branched (C
1-C
6) alkylidene group, and R
13, R
14And R
15As the preamble definition,
-R
17Expression (C
3-C
6) cycloalkyl,
-X
5The expression be selected from singly-bound ,-CH
2-, Sauerstoffatom, optional through one or two sulphur atom that Sauerstoffatom replaced and through hydrogen atom or (C
1-C
6) group of the nitrogen-atoms that alkyl replaced,
-R
18Expression is selected from the group of heteroaryl, cycloalkyl, Heterocyclylalkyl, these groups are 5 or 6-person's monocycle or the dicyclo be made up of two 5-or 6-person's monocycle, it is chosen wantonly and replaces through one or more group, and described substituting group is identical or different independently of one another, and is selected from (C
1-C
6) alkyl, halogen, hydroxyl, oxo, cyano group, tetrazyl, amino and-C (=O) OR
7, R wherein
7Expression hydrogen or (C
1-C
6) alkyl,
-X
6Expression is selected from-CH
2-, optional through one or two sulphur atom that Sauerstoffatom replaced and through hydrogen atom or (C
1-C
6) group of the nitrogen-atoms that alkyl replaced,
-R
21Expression is optional through the phenyl that one or more group replaced, and described substituting group can be identical or different independently of one another, and be selected from (C
1-C
6) alkyl, halogen, hydroxyl, cyano group, tetrazyl, amino and-C (=O) OR
7, R wherein
7Expression hydrogen or (C
1-C
6) alkyl,
And X
1, X
2, X
3, G
1, m and R
2As definition in the general formula (I),
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
6. compound as claimed in claim 1, wherein:
R
1The group of expression general formula (i/d):
Z wherein
2, p, B, G
3And define in q such as general formula (I) compound,
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
7. compound as claimed in claim 6, wherein Z
2Expression-CR
11R
12, R wherein
11And R
12The expression hydrogen atom,
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
8. compound as claimed in claim 6, wherein p is 1,
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
9. compound as claimed in claim 6, wherein B represents phenyl, q equals 0 or 1, and G
3, when it exists, represent to be selected from OR
13, halogen, S (O)
K1R
13And (CH
2)
kC (=O) OR
13Group, R wherein
13Expression hydrogen atom or (C
1-C
6) alkyl, k is 0, and k1 is 2,
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
10. compound as claimed in claim 1, wherein G
1The group of expression general formula (i/a), wherein R
4Expression hydrogen atom or methyl, or the group of general formula (i/b), wherein R
4And R
5Identical and respectively represent hydrogen atom or methyl, and R
6Expression hydrogen atom or methyl,
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
11. compound as claimed in claim 1, wherein X
1Expression group-CR
3, R wherein
3The expression hydrogen atom, X
2Expression nitrogen-atoms or group-CR
3, R wherein
3Expression hydrogen atom, and X
3Expression group-CR
3, R wherein
3The expression hydrogen atom,
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
12. compound as claimed in claim 1, wherein G
2The group of expression carbon-to-carbon triple bond or general formula (i/a), wherein Y
1Expression Sauerstoffatom, and Y
2Expression group-NH,
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
13. compound as claimed in claim 1, wherein Z
1Expression-CR
9R
10, R wherein
9And R
10Represent hydrogen atom separately, and n is 1,
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
14. compound as claimed in claim 1, wherein A represents to be selected from the group of phenyl and pyridyl, and m is 0 or 1, and R
2Expression (C
1-C
6) compound of alkoxyl group or hydrogen atom,
Randomly its racemization form, its isomer, its N-oxide compound and pharmaceutically useful salt thereof.
15. compound as claimed in claim 1, it is to be selected from:
3-(4-methoxyl group-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides
3-(4-methoxyl group-benzyl)-2-methyl-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides, hydrochloride
3-(4-methoxyl group-benzyl)-1-methyl-4-oxo-1,2,3,4-tetrahydrochysene-quinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides
3-(4-methoxyl group-benzyl)-1,2,2-trimethylammonium-4-oxo-1,2,3,4-tetrahydrochysene-quinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides
4-[6-(4-methoxyl group-benzyl amido formyl radical)-4-oxo-1,4-dihydro-2H-quinazoline-3-ylmethyl]-phenylformic acid
4-[6-(4-methoxyl group-benzyl amido formyl radical)-1-methyl-4-oxo-1,4-dihydro-2H-quinazoline-3-ylmethyl]-methyl benzoate
4-[6-(4-methoxyl group-benzyl amido formyl radical)-1-methyl-4-oxo-1,4-dihydro-2H-quinazoline-3-ylmethyl]-phenylformic acid
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 3-methoxy-benzyl acid amides
3-(4-methylsulfonyl)-benzyl-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxy-benzyl acid amides
4-oxo-3-[4-(tetramethyleneimine-1-alkylsulfonyl)-benzyl]-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides
4-[6-(3-methoxyl group-benzyl amido formyl radical)-4-oxo-4H-quinazoline-3-ylmethyl]-phenylformic acid
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid (2-methoxyl group-pyridin-4-yl methyl)-acid amides
3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 3-methoxyl group-benzyl acid amides
3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 4-methoxyl group-benzyl acid amides
3-(3,4-two fluoro-benzyls)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid (2-methoxyl group-pyridin-4-yl methyl)-acid amides reaches
3-(3,4-two fluoro-benzyls)-4-oxo-3,4-dihydro-chinazoline-6-carboxylic acid 4-methoxyl group-benzyl acid amides
16. compound as claimed in claim 1, it is to be selected from:
3-(4-luorobenzyl)-6-(3-phenyl-third-1-alkynyl)-3H-quinazoline-4-one,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-methyl benzoate,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid,
3-(4-luorobenzyl)-6-(3-phenyl-third-1-alkynyl)-3H-pyrido [3,4-d] pyrimidin-4-one,
4-[6-(3-phenyl-third-1-alkynyl)-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl] methyl benzoate,
4-[6-(3-phenyl-third-1-alkynyl)-4-oxo-4H-pyrido [3,4-d] pyrimidin-3-yl methyl] phenylformic acid,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H quinazoline-3-ylmethyl]-phenylformic acid,
4-{6-[3-(4-p-methoxy-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzamide,
3-[(3,5-two fluoro-4-hydroxyls)-benzyl]-6-(3-phenyl-third-1-alkynyl)-3H-quinazoline-4-one
4-[6-(3-imidazoles-1-base-third-1-alkynyl)-4-oxo-4H-quinazoline-3-ylmethyl]-phenylformic acid,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzsulfamide,
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzonitrile,
3-(3-chloro-benzyl)-6-(4-phenyl-Ding-1-alkynyl)-3H-quinazoline-4-one,
3-(3-chloro-benzyl)-6-(3-phenyl-third-1-alkynyl)-3H-quinazoline-4-one,
4-[4-oxo-6-(3-pyrazol-1-yl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid,
6-(3-phenyl-third-1-alkynyl)-3-[4-(1H-tetrazolium-5-yl)-benzyl]-the 3H-quinazoline-4-one,
3-(3,4-two fluoro-benzyls)-6-[3-(pyridin-4-yl oxygen)-third-1-alkynyl]-the 3H-quinazoline-4-one,
3-(3,4-two fluoro-benzyls)-6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
N-{4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenyl }-ethanamide,
3-(3,4-two fluoro-benzyls)-6-(3-phenyl-third-1-alkynyl)-3H-quinazoline-4-one,
3-(4-ethanoyl-benzyl)-6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one,
6-(3-phenyl-third-1-alkynyl)-3-pyridin-4-yl methyl-3H-quinazoline-4-one reaches
6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-3-pyridin-4-yl methyl-3H-quinazoline-4-one.
17. compound as claimed in claim 1, it is to be selected from:
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-methyl benzoate
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenylformic acid
4-[6-(3-methoxyl group-benzyl amido formyl radical)-4-oxo-4H-quinazoline-3-ylmethyl]-phenylformic acid
4-{6-[3-(4-p-methoxy-phenyl)-third-1-alkynyl]-4-oxo-4H-quinazoline-3-ylmethyl }-phenylformic acid
3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 3-methoxyl group-benzyl acid amides
3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido [3,4-d] pyrimidine-6-carboxylic acid 4-methoxyl group-benzyl acid amides
4-[6-(3-imidazoles-1-base-third-1-alkynyl)-4-oxo-4H-quinazoline-3-ylmethyl]-phenylformic acid
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzsulfamide
4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-benzonitrile
6-(3-phenyl-third-1-alkynyl)-3-[4-(1H-tetrazolium-5-yl)-benzyl]-the 3H-quinazoline-4-one
3-(3,4-two fluoro-benzyls)-6-[3-(pyridin-4-yl oxygen)-third-1-alkynyl]-the 3H-quinazoline-4-one
3-(3,4-two fluoro-benzyls)-6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one
N-{4-[4-oxo-6-(3-phenyl-third-1-alkynyl)-4H-quinazoline-3-ylmethyl]-phenyl }-ethanamide
3-(4-ethanoyl-benzyl)-6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-the 3H-quinazoline-4-one
6-(3-phenyl-third-1-alkynyl)-3-pyridin-4-yl methyl-3H-quinazoline-4-one reaches
6-[3-(4-methoxyl group-phenyl)-third-1-alkynyl]-3-pyridin-4-yl methyl-3H-quinazoline-4-one.
18. a method for preparing compound as claimed in claim 1, it uses general formula (II) compound with as initial substance:
X wherein
1, X
2, X
3And Y
1Be identical definition in general formula (I) compound that has with claim 1, and T represent group (C
1-C
6) alkyl,
General formula (II) compound uses general formula (III) compound to handle:
Z wherein
1, Y
2, R
2, A, n and m have with general formula (I) compound in identical definition,
By in the presence of diisopropylethylamine and solvent, activate this acid function with activator, produce the compound of general formula (IV):
X wherein
1, X
2, X
3, Y
1, T, Z
1, Y
2, R
2, A, n and m such as preamble define,
Ester group is through hydrolysis in general formula (IV) compound, and the compound of gained is at alkali and general formula R
1-NH
2(R wherein
1As defining in general formula (I) compound) primary amine exist down with Treatment with activating agent,
Produce logical formula V compound:
X wherein
1, X
2, X
3, Y
1, Y
2, Z
1, R
2, R
1, A, n and m such as preamble define, this logical formula V compound is to handle through following manner:
● under heating condition, use triethyl orthoformate to handle, produce the compound of general formula (I/a), it is the special case of general formula (I):
X wherein
1, X
2, X
3, Y
1, Y
2, Z
1, R
2, R
1, A, n and m such as preamble define,
● or under heating condition, in the presence of acid, with general formula (VI) compound treatment:
R wherein
4Have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/b), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, Y
1, Y
2, Z
1, R
2, R
1, R
4, A, n and m such as preamble define,
● or under alkaline condition, use general formula (VII) compound treatment:
R wherein
4And R
5Have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/c), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, Y
1, Y
2, Z
1, R
2, R
1, R
4, R
5, A, n and m such as preamble define,
This general formula (I/c) compound is chosen wantonly in the presence of general formula (VIII) compound, uses hydride to handle:
R
6-Hal (VIII)
R wherein
6Have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/d), it is the special case of general formula (I) compound:
X wherein
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 such as preamble define,
General formula (I/a), (I/b), (I/c) and compound component part The compounds of this invention (I/d), it optionally carries out purifying according to conventional purification technique, optionally be separated into different isomer, and optionally use pharmaceutically useful acid or alkali to change into additive salt or change into its N-oxide compound according to conventional isolation technique.
19. a method for preparing the compound of claim 1, it uses general formula (X) compound as initial substance:
X wherein
1, X
2And X
3Have with general formula (I) compound in identical definition, and Hal represents halogen atom,
This general formula (X) compound uses the derivative of phosgene to handle in first step, to produce the compound of general formula (XI):
X wherein
1, X
2, X
3Reach Hal such as preamble and define,
This general formula (XI) compound uses general formula R in alkaline medium
1The primary amine of-NH (R wherein
1Have with general formula (I) compound in identical definition) handle, produce the compound of general formula (XII):
X wherein
1, X
2, X
3, R
1Reach Hal such as preamble and define,
This general formula (XII) compound is handled in such a way:
● under heating condition, use triethyl orthoformate to handle, to produce the compound of general formula (XIII/a):
X wherein
1, X
2, X
3, R
1Reach Hal such as preamble and define,
● or under heating condition, in the presence of acid, use general formula (VI) compound to handle:
R wherein
4Have with general formula (I) compound in identical definition,
Produce the compound of general formula (XIII/b):
X wherein
1, X
2, X
3, Hal, R
1And R
4As the preamble definition,
● or under alkaline condition, use general formula (VII) compound treatment:
R wherein
4And R
5Have with general formula (I) compound in identical definition,
Produce the compound of general formula (XIII/c):
X wherein
1, X
2, X
3, Hal, R
1, R
4And R
5As the preamble definition,
The compound of this general formula (XIII/c) is chosen wantonly in the presence of general formula (XIII) compound, uses hydride to handle:
R
6-Hal (VIII)
R wherein
6Have with general formula (I) compound in identical definition, and Hal is halogen,
Produce the compound of general formula (XIII/b), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, Hal, R
1, R
4, R
5And R
6As the preamble definition,
General formula (XIII/a), (XIII/b), (XIII/c) and compound (XIII/d) constitute the compound of general formula (XIII/e):
X wherein
1, X
2, X
3, Hal, R
1And G
1Suc as formula defining in (I) compound,
This general formula (XIII/e) compound uses general formula (XIV) compound to handle under via palladium-catalyzed alkynyl condition:
Z wherein
1, R
2, A, n and m have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/e), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, R
1, G
1, Z
1, R
2, A, n and m have with general formula (I) compound in identical definition,
General formula (I/e) compound component part The compounds of this invention, it is optionally to carry out purifying according to conventional purification technique, optionally be separated into different isomer, and optionally use pharmaceutically useful acid or alkali to change into additive salt or change into its N-oxide compound according to conventional isolation technique.
20. a method for preparing the compound of claim 1, it uses general formula (XIII/e) compound as initial substance:
X wherein
1, X
2, X
3, R
1And G
1As defining in general formula (I) compound, and Hal is halogen atom,
General formula (XIII/e) compound is at two (triphenyl phosphine) palladiums of dichloro, cupric iodide and N, and N '-diisopropylethylamine exists down, in dimethyl formamide, is condensed on the compound of general formula (XV):
Z wherein
1, R
2, A, n and m have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/e), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, R
1, G
1, Z
1, R
2, A, n and m have with general formula (I) compound in identical definition.
21. a method for preparing the compound of claim 1, it uses general formula (XIII/e) compound as initial substance:
X wherein
1, X
2, X
3, R
1And G
1As defining in general formula (I) compound, and Hal is halogen atom,
The compound of general formula (XIII/e) in the presence of protic solvent such as methyl alcohol and catalytic amount palladium, with reaction of carbon monoxide, produces the compound of general formula (XVI) in alkaline media:
X wherein
1, X
2, X
3, R
1And G
1As defining in general formula (I) compound,
The hydrolysis in alkaline medium of general formula (XVI) compound, the compound of generation general formula (XVII):
X wherein
1, X
2, X
3, R
1And G
1As defining in general formula (I) compound,
The compound of general formula (XVII) in the presence of Mukayama reagent, is condensed on general formula (XVIII) compound in alkaline medium:
Z wherein
1, R
2, A, n and m have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/f), it is the special case of general formula (I) compound:
X wherein
1, X
2, X
3, Z
1, R
2, R
1, A, n and m define as preamble,
The compound component part The compounds of this invention of general formula (I/f), it is optionally to carry out purifying according to conventional purification technique, optionally be separated into different isomer, and optionally use pharmaceutically useful acid or alkali to change into additive salt or change into its N-oxide compound according to conventional isolation technique.
22. a method for preparing the compound of claim 1, it uses general formula (XIX) compound as initial substance:
Wherein Hal represents halogen atom,
General formula (XIX) compound reacts in the presence of polar solvent in the presence of carbonamidine, produces the compound of general formula (XX):
Wherein Hal such as preamble define
The compound of general formula (XX) uses general formula R in alkaline medium
1-Hal compound (R wherein
1As defining in general formula (I) compound, and Hal represents halogen atom) handle, produce the compound of general formula (XXI):
Wherein Hal and R
1As the preamble definition,
The compound of general formula (XXI) in the presence of alcoholic solvent and catalytic amount palladium, reacts with carbon monoxide in alkaline medium, produces the compound of general formula (XXII):
R wherein
1As the preamble definition,
The compound of general formula (XXII) in the presence of trimethyl aluminium, and the compound condensation of general formula (XVIII):
Z wherein
1, R
2, A, n and m have with general formula (I) compound in identical definition,
Produce the compound of general formula (I/g), it is the special case of general formula (I) compound:
Z wherein
1, R
2, R
1, A, n and m be as preceding definition,
The compound component part The compounds of this invention of general formula (I/g), it is optionally to carry out purifying according to conventional purification technique, optionally be separated into different isomer, and optionally use pharmaceutically useful acid or alkali to change into additive salt or change into its N-oxide compound according to conventional isolation technique.
23. a treatment suffers from the method for the life entity of disease, wherein relates to the inhibition of the 13rd type matrix metalloproteinase, described method comprises the step of compound of life entity being used the claim 1 of this patient's condition amount of effectively releiving.
24. a treatment suffers from the method for the life entity of disease, described method comprises the step of compound of life entity being used the claim 1 of this patient's condition amount of effectively releiving, and described disease is selected from sacroiliitis, rheumatic arthritis, osteoarthritis, osteoporosis, periodontopathy, inflammatory bowel, psoriasis, multiple sclerosis, cardiac insufficiency, arteriosclerosis, asthma, chronic obstructive pulmonary disease, macular degeneration and the cancer relevant with the age.
25. a pharmaceutical composition, its compound as claimed in claim 1 that comprises significant quantity are with as activeconstituents, this composition is to use separately or be used in combination with one or more pharmaceutically acceptable vehicle or carrier.
26. a pharmaceutical composition that is used for claim 23 method, its compound as claimed in claim 1 that comprises significant quantity is with as activeconstituents and one or more pharmaceutically useful vehicle or carrier.
27. a pharmaceutical composition that is used for claim 23 method, its compound of claim 16 that comprises significant quantity is with as activeconstituents, and one or more pharmaceutically useful vehicle or carrier.
28. a pharmaceutical composition that is used for claim 23 method, its compound of claim 17 that comprises significant quantity is with as activeconstituents, and one or more pharmaceutically useful vehicle or carrier.
29. the compound of claim 1 is used for the treatment of purposes in the pharmaceutical prod of disease in preparation, described disease treatment relates to the inhibition of the 13rd type matrix metalloproteinase.
30. the purposes of claim 29, wherein said disease are sacroiliitis, rheumatic arthritis, osteoarthritis, osteoporosis, periodontopathy, inflammatory bowel, psoriasis, multiple sclerosis, cardiac insufficiency, arteriosclerosis, asthma, chronic obstructive pulmonary disease, macular degeneration and the cancer relevant with the age.
31. the purposes of claim 30, wherein this disease is a sacroiliitis.
32. the purposes of claim 30, wherein this disease is an osteoarthritis.
33. the purposes of claim 30, wherein this disease is a rheumatic arthritis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2002/003240 WO2003076416A1 (en) | 2002-03-08 | 2002-03-08 | Oxo azabicyclic compounds |
| EPPCT/EP02/03240 | 2002-03-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1738806A true CN1738806A (en) | 2006-02-22 |
Family
ID=27798761
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA038048752A Pending CN1738806A (en) | 2002-03-08 | 2003-03-06 | Oxo-azabicyclic compounds |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP1492775A2 (en) |
| JP (1) | JP2005526070A (en) |
| KR (1) | KR20040095270A (en) |
| CN (1) | CN1738806A (en) |
| AP (1) | AP2004003125A0 (en) |
| AR (1) | AR039562A1 (en) |
| AU (2) | AU2002249275A1 (en) |
| BR (1) | BR0308280A (en) |
| CA (1) | CA2478706A1 (en) |
| CO (1) | CO5601020A2 (en) |
| EA (1) | EA200401053A1 (en) |
| EC (1) | ECSP045278A (en) |
| IL (1) | IL163818A0 (en) |
| IS (1) | IS7414A (en) |
| MA (1) | MA27183A1 (en) |
| MX (1) | MXPA04008681A (en) |
| NO (1) | NO20044041L (en) |
| OA (1) | OA12782A (en) |
| PA (1) | PA8568501A1 (en) |
| PE (1) | PE20031018A1 (en) |
| PL (1) | PL372622A1 (en) |
| SV (1) | SV2003001495A (en) |
| TN (1) | TNSN04169A1 (en) |
| UY (1) | UY27700A1 (en) |
| WO (2) | WO2003076416A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8148376B2 (en) | 2006-10-05 | 2012-04-03 | Gilead Sciences, Inc. | 3, 4-dihydroquinoxalin-2(1H)-ones for use as stearoyl CoA desaturase inhibitors |
| CN103524431A (en) * | 2013-09-24 | 2014-01-22 | 西安交通大学 | 3-benzyl-4-quinazolinone compound as well as synthetic method and applications thereof |
| CN108495857A (en) * | 2016-01-14 | 2018-09-04 | 法国施维雅药厂 | New phospha cyclohexane class compound and azepine phospha cyclohexane class compound, their preparation method and the Pharmaceutical composition comprising them |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PA8539501A1 (en) | 2001-02-14 | 2002-09-30 | Warner Lambert Co | TRIAZOLO COMPOUNDS AS MMP INHIBITORS |
| US6962922B2 (en) | 2001-10-12 | 2005-11-08 | Warner-Lambert Company Llc | Alkynylated quinazoline compounds |
| US6894057B2 (en) | 2002-03-08 | 2005-05-17 | Warner-Lambert Company | Oxo-azabicyclic compounds |
| AU2003253150A1 (en) | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | Chromone derivatives as matrix metalloproteinase inhibitors |
| JP2006501215A (en) | 2002-08-13 | 2006-01-12 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | Monocyclic derivatives as matrix metalloproteinase inhibitors |
| WO2004014378A1 (en) | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | 3-isoquinolinone derivatives as matrix metalloproteinase inhiitors |
| WO2004014375A2 (en) | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Fused bicyclic metalloproteinase inhibitors |
| PA8578101A1 (en) | 2002-08-13 | 2004-05-07 | Warner Lambert Co | HETEROBIARILO DERIVATIVES AS METALOPROTEINASE IN MATRIX INHIBITORS |
| AU2003250470A1 (en) | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | Pyrimidinone fused bicyclic metalloproteinase inhibitors |
| WO2004014384A2 (en) * | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Cyclic compounds containing zinc binding groups as matrix metalloproteinase inhibitors |
| AU2003250471A1 (en) | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | Pyrimidine-2,4-dione derivatives as matrix metalloproteinase inhibitors |
| AU2003253186A1 (en) | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | Fused tetrahydropyridine derivatives as matrix metalloproteinase inhibitors |
| BR0313724A (en) | 2002-08-13 | 2005-06-28 | Warner Lambert Co | Azaisoquinoline derivatives as matrix metalloproteinase inhibitors |
| WO2005016926A1 (en) * | 2003-08-19 | 2005-02-24 | Warner-Lambert Company Llc | Pyrido [3,4-d] pyrimidine derivatives as matrix metalloproteinase-13 inhibitors |
| DE10360835A1 (en) * | 2003-12-23 | 2005-07-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New bicyclic imidazole derivatives are dipeptidylpeptidase-IV inhibitors useful to treat e.g. arthritis, obesity, allograft transplantation and calcitonin-induced osteoporosis |
| MXPA06012333A (en) * | 2004-04-30 | 2007-01-17 | Takeda Pharmaceutical | Heterocyclic amide compound and use thereof as an mmp-13 inhibitor. |
| CN101001845A (en) * | 2004-06-15 | 2007-07-18 | 阿斯利康(瑞典)有限公司 | Substituted quinazolones as anti-cancer agents. |
| WO2012052451A1 (en) | 2010-10-18 | 2012-04-26 | Merz Pharma Gmbh & Co. Kgaa | Metabotropic glutamate receptor modulators |
| JO3512B1 (en) | 2014-03-26 | 2020-07-05 | Astex Therapeutics Ltd | Quinoxaline derivatives useful as fgfr kinase modulators |
| CN108137546B (en) | 2015-09-23 | 2021-07-27 | 詹森药业有限公司 | Bis-heteroaryl substituted 1, 4-benzodiazepine compounds and their use for the treatment of cancer |
| JP6898919B2 (en) | 2015-09-23 | 2021-07-07 | ヤンセン ファーマシューティカ エヌ．ベー． | New compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0946095A1 (en) * | 1996-12-17 | 1999-10-06 | E.I. Du Pont De Nemours And Company | Fungicidal quinazolinones |
| PA8539401A1 (en) * | 2001-02-14 | 2002-10-28 | Warner Lambert Co | QUINAZOLINAS AS INHIBITORS OF MMP-13 |
| PA8539301A1 (en) * | 2001-02-14 | 2002-09-30 | Warner Lambert Co | INHIBITORS OF THE METALOPROTEINASE OF THE MATRIX |
-
2002
- 2002-03-08 AU AU2002249275A patent/AU2002249275A1/en not_active Abandoned
- 2002-03-08 WO PCT/EP2002/003240 patent/WO2003076416A1/en not_active Application Discontinuation
-
2003
- 2003-03-04 SV SV2003001495A patent/SV2003001495A/en not_active Application Discontinuation
- 2003-03-06 BR BR0308280-6A patent/BR0308280A/en not_active IP Right Cessation
- 2003-03-06 CN CNA038048752A patent/CN1738806A/en active Pending
- 2003-03-06 EP EP03708181A patent/EP1492775A2/en not_active Withdrawn
- 2003-03-06 OA OA1200400234A patent/OA12782A/en unknown
- 2003-03-06 AU AU2003212307A patent/AU2003212307A1/en not_active Abandoned
- 2003-03-06 EA EA200401053A patent/EA200401053A1/en unknown
- 2003-03-06 AP APAP/P/2004/003125A patent/AP2004003125A0/en unknown
- 2003-03-06 PE PE2003000218A patent/PE20031018A1/en not_active Application Discontinuation
- 2003-03-06 PL PL03372622A patent/PL372622A1/en not_active Application Discontinuation
- 2003-03-06 KR KR10-2004-7013994A patent/KR20040095270A/en not_active Application Discontinuation
- 2003-03-06 PA PA20038568501A patent/PA8568501A1/en unknown
- 2003-03-06 CA CA002478706A patent/CA2478706A1/en not_active Abandoned
- 2003-03-06 MX MXPA04008681A patent/MXPA04008681A/en unknown
- 2003-03-06 WO PCT/EP2003/002277 patent/WO2003076417A2/en not_active Application Discontinuation
- 2003-03-06 UY UY27700A patent/UY27700A1/en not_active Application Discontinuation
- 2003-03-06 IL IL16381803A patent/IL163818A0/en unknown
- 2003-03-06 AR ARP030100749A patent/AR039562A1/en not_active Application Discontinuation
- 2003-03-06 JP JP2003574636A patent/JP2005526070A/en not_active Withdrawn
-
2004
- 2004-08-19 IS IS7414A patent/IS7414A/en unknown
- 2004-08-25 CO CO04082792A patent/CO5601020A2/en not_active Application Discontinuation
- 2004-08-31 MA MA27842A patent/MA27183A1/en unknown
- 2004-09-03 EC EC2004005278A patent/ECSP045278A/en unknown
- 2004-09-03 TN TNP2004000169A patent/TNSN04169A1/en unknown
- 2004-09-24 NO NO20044041A patent/NO20044041L/en not_active Application Discontinuation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8148376B2 (en) | 2006-10-05 | 2012-04-03 | Gilead Sciences, Inc. | 3, 4-dihydroquinoxalin-2(1H)-ones for use as stearoyl CoA desaturase inhibitors |
| CN103524431A (en) * | 2013-09-24 | 2014-01-22 | 西安交通大学 | 3-benzyl-4-quinazolinone compound as well as synthetic method and applications thereof |
| CN108495857A (en) * | 2016-01-14 | 2018-09-04 | 法国施维雅药厂 | New phospha cyclohexane class compound and azepine phospha cyclohexane class compound, their preparation method and the Pharmaceutical composition comprising them |
Also Published As
| Publication number | Publication date |
|---|---|
| CO5601020A2 (en) | 2006-01-31 |
| TNSN04169A1 (en) | 2007-03-12 |
| WO2003076417A3 (en) | 2003-11-13 |
| AU2003212307A1 (en) | 2003-09-22 |
| JP2005526070A (en) | 2005-09-02 |
| CA2478706A1 (en) | 2003-09-18 |
| EP1492775A2 (en) | 2005-01-05 |
| AP2004003125A0 (en) | 2004-09-30 |
| SV2003001495A (en) | 2003-11-04 |
| PA8568501A1 (en) | 2003-12-19 |
| EA200401053A1 (en) | 2005-04-28 |
| MXPA04008681A (en) | 2004-12-06 |
| AR039562A1 (en) | 2005-02-23 |
| WO2003076417A2 (en) | 2003-09-18 |
| OA12782A (en) | 2006-07-10 |
| NO20044041L (en) | 2004-10-07 |
| PL372622A1 (en) | 2005-07-25 |
| BR0308280A (en) | 2004-12-28 |
| ECSP045278A (en) | 2004-10-26 |
| UY27700A1 (en) | 2003-10-31 |
| IL163818A0 (en) | 2005-12-18 |
| MA27183A1 (en) | 2005-01-03 |
| AU2002249275A1 (en) | 2003-09-22 |
| IS7414A (en) | 2004-08-19 |
| PE20031018A1 (en) | 2004-01-09 |
| KR20040095270A (en) | 2004-11-12 |
| WO2003076416A1 (en) | 2003-09-18 |
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