CN1714083A - Novel pyrimidine-4,6-dicarboxamides for the selective inhibition of collagenases - Google Patents

Abstract

Pyrimidine-4,6-dicarboxamides of formula (I), are suitable for the selective inhibition of collagenase (MMP 13). The pyrimidine-4,6-dicarboxamides can thus be used for the treatment of degenerative joint diseases.

Description

Novel pyrimidine-4,6-dicarboxylic acid diamides for selective inhibition of collagenase

The present invention relates to novel pyrimidine-4,6-dicarboxylic acid diamides and their use for the selective inhibition of collagenase (MMP13). Therefore, pyrimidine-4,6-dicarboxylic acid diamides are useful in the treatment of degenerative joint diseases.

Pyrimidine-4,6-dicarboxylic acid diamides and 2,4-substituted pyridine N-oxides are known to inhibit the enzymes proline hydroxylase and lysine hydroxylase, thus inhibiting collagen-specific hydroxylation Inhibition of collagen biosynthesis by affecting the reaction (EP 0418797; EP 0463592). Inhibition of this collagen biosynthesis leads to the formation of nonfunctional, underhydroxylated collagen molecules, which the cell releases only in minor amounts into the extracellular space. Furthermore, under-hydroxylated collagen cannot incorporate into the collagen matrix and is very prone to proteolytic degradation. As a result of these effects, the total amount of extracellularly deposited collagen is reduced. It is known from patent applications WO 02/064571 and WO 02/064080 that certain pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic acid diamides can be allosteric inhibitors of MMP13.

In diseases such as osteoarthritis and rheumatism, destruction of the joints occurs, caused inter alia by the proteolysis of collagen by collagenase. Collagenases belong to the metalloproteinase (MP) or matrix metalloproteinase (MMP) superfamily. Under physiological conditions, MMPs cleave collagen, laminin, proteoglycans, elastin or gelatin and thus play an important role in bone and connective tissue. A number of different inhibitors of MMPs and/or collagenases have been disclosed (EP 0 606 046; WO 94/28889). Known MMP inhibitors generally suffer from a lack of specificity when only one MMP needs to be inhibited. As a result, most MMP inhibitors inhibit several MMPs simultaneously because the structures of the catalytic domains are similar among MMPs. Accordingly, inhibitors have adverse action properties for many enzymes, including those with important functions (Massova I. et al., The FASEB Journal (1998) 12, 1075-1095).

In the search for effective compounds for the treatment of connective tissue diseases, it was found that the compounds used in the present invention are potent inhibitors of matrix metalloproteinase 13, while having essentially no effect on MMP 3 and 8.

Accordingly, the present invention relates to compounds of formula I

and/or all stereoisomeric forms of compounds of formula I and/or mixtures of these forms in any proportion and/or physiologically tolerable salts of compounds of formula I, wherein

For case a)

R1 is a hydrogen atom or -(C ₁ -C ₆ )-alkyl,

R2 is -(C ₁ -C ₆ )-alkyl, wherein the alkyl is substituted once, twice or three times by the following substituents

1.-(C ₁ -C ₆ )-alkyl-O-(C ₆ -C ₁₄ )-aryl,

2.-(C ₀ -C ₆ )-Alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkyl, wherein R8 is

i) a hydrogen atom or

ii) -(C ₁ -C ₆ )-alkyl,

3.-C(O)-N(R9)-(R10), wherein R9 and R10 are identical or different and independently of each other:

i) a hydrogen atom or

ii) -(C ₁ -C ₆ )-alkyl, or

R9 and R10 form a 5-, 6- or 7-membered saturated ring together with the nitrogen atom to which they are attached, wherein heteroatoms selected from oxygen, sulfur and nitrogen can also replace one or two additional carbon atoms, in nitrogen In the case of , the nitrogen atoms can independently of each other be unsubstituted or substituted by (C ₁ -C ₆ )-alkyl,

4. -(C ₆ -C ₁₄ )-aryl, wherein aryl is substituted independently of one another once/twice or three times by the following substituents:

4.1) -CH ₂ -C(O)-O-R8, wherein R8 has the meanings stated above,

4.2)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings stated above,

4.3)-(C ₀ -C ₆ )-Alkyl-C(O)-NH-CN,

4.4)-O-(C ₀ -C ₆ )-alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings stated above,

4.5)-S(O) _y- (C ₁ -C ₆ )-alkyl-C(O)-O-R8, wherein R8 has the meanings stated above and y is 1 or 2,

4.6)-S(O) _z- (C ₁ -C ₆ )-Alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings stated above and z is 0,1 or 2,

4.7)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-N(R9)-(R10), wherein R8, R9 and R10 has the meaning stated above,

4.8)-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-Het, wherein R8 has the above-mentioned meaning and Het is saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring systems containing 1, 2 or 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, and are unsubstituted or substituted once or twice independently of each other by the following substituents or three times:

a) halogen,

b) cyano,

c) nitro,

d) hydroxyl,

e) amino groups,

f)-C(O)-O-(C ₁ -C ₆ )-alkyl,

g)-C(O)-OH,

h) -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or three times by halogen,

i) -O-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or substituted independently of each other once, twice or three times by halogen,

4.9)-C(O)-N(R8)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or independently of each other mentioned above The groups a) to i) are substituted once, twice or three times,

4.10)-CH2 _- N(R9)-(R10), wherein R9 and R10 have the meanings mentioned above,

4.11) -(CH ₂ ) _y -N(R8)-C(O)-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or independently of each other by the groups mentioned above a) to i) substitution once, twice or three times and y is 1 or 2,

4.12)-(CH ₂ ) _x -N(R8)-C(O)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, where the aryl groups are unsubstituted or mutually independently substituted one, two or three times by the groups a) to i) mentioned above and x is 0, 1, 2, 3 or 4,

4.13) -(CH ₂ ) _x -N(R8)-C(O)-(C ₀ -C ₆ )-alkyl-Het, wherein Het is unsubstituted or independently of each other by the above-mentioned groups a ) to i) are substituted once, twice or three times and x is 0, 1, 2, 3 or 4,

4.14) -(CH ₂ ) _x -N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkyl, wherein the alkyl group is unsubstituted or independently of each other by the above-mentioned groups a) to i) are substituted once, twice or three times and x is 0, 1, 2, 3 or 4,

4.15)-(CH ₂ ) _x -N(R8)-C(O)-O-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or independently of each other one, two or three times by the groups a) to i) mentioned above and x is 0, 1, 2, 3 or 4,

4.16) -(CH ₂ ) _x -N(R8)-C(O)-O-(C ₀ -C ₆ )-alkyl-Het, wherein Het is unsubstituted or independently of each other by the above-mentioned groups Groups a) to i) are substituted once, twice or three times and x is 0, 1, 2, 3 or 4,

4.17)-( _CH2 ) _x -N(R8)-C(O)-N(R11)-R12, wherein R8 and x have the meanings stated above, R11 and R12 are identical or different and independently of each other are:

4.17.1) Hydrogen atoms,

4.17.2) -(C ₁ -C ₆ )-Alkyl,

4.17.3)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or independently of one another by the groups a) to i) mentioned above instead of once, twice or thrice,

4.17.4)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or substituted independently of each other once, twice or three times by the groups a) to i) mentioned above,

4.17.5)-C(O)-(C ₁ -C ₆ )-alkyl,

4.17.6)-C(O)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl,

4.17.7)-C(O)-(C ₀ -C ₆ )-Alkyl-Het,

4.17.8) -SO ₂ -(C ₁ -C ₆ )-alkyl,

4.17.9) -SO ₂ -(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl,

4.17.10) -SO ₂ -(C ₀ -C ₆ )-alkyl-Het,

4.18)-(CH ₂ ) _x -N(R8)-S(O) _2- (C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or are substituted one, two or three times independently of one another by the groups a) to i) mentioned above and x and R8 have the meanings stated above,

4.19) -(CH ₂ ) _x -N(R8)-S(O) ₂ -(C ₀ -C ₆ )-alkyl-Het, wherein Het is unsubstituted or independently of each other by the above-mentioned groups a) to i) are substituted once, twice or three times and x and R8 have the meanings stated above,

4.20)-(CH ₂ ) _x -N(R8)-S(O) ₂ -N(R8)-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or independently of each other mentioned above The radicals a) to i) are substituted once, twice or three times and x and R8 independently of one another have the meanings stated above,

4.21)-(CH ₂ ) _x -N(R8)-S(O) ₂ -N(R8)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or substituted independently of each other once, twice or three times by the groups a) to i) mentioned above and x and R8 independently of each other have the meanings stated above,

4.22) -(CH ₂ ) _x -N(R8)-S(O) ₂ -N(R8)-(C ₀ -C ₆ )-alkyl-Het, wherein Het is unsubstituted or independently of each other replaced by the above The groups a) to i) mentioned are substituted once, twice or three times and x and R8 independently of one another have the meanings stated above,

4.23)-(CH ₂ ) _x -N(R8)-C(O)-N(R8)-SO ₂ -R ₁₃ , wherein x and R8 independently of each other have the above-mentioned meanings and R13 is -(C ₁ -C ₆ )-alkyl or -(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl,

4.24)-S(O) ₂ -N(R8)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or independently of each other mentioned above The radicals a) to i) are substituted once, twice or three times and R8 has the meanings stated above,

4.25) S(O) ₂ -N(R8)-(C ₀ -C ₆ )-alkyl-Het, wherein Het is unsubstituted or substituted once independently of each other by the groups a) to i) mentioned above , twice or three times and R8 has the above-mentioned meaning,

4.26) -S(O) ₂ -N(R8)-(C ₁ -C ₆ )-Alkyl, wherein the alkyl group is unsubstituted or substituted once independently of each other by the groups a) to i) mentioned above , twice or three times and R8 has the above-mentioned meaning,

4.27) -S(O) ₂ -(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or independently of each other by the above-mentioned groups a ) to i) replace once, twice or three times,

4.28) -S(O) ₂ -(C ₀ -C ₆ )-alkyl-Het, wherein Het is unsubstituted or substituted independently of each other by the groups a) to i) mentioned above once, twice or three times,

4.29)-O-Het, wherein Het is unsubstituted or substituted one, two or three times independently of each other by the groups a) to i) mentioned above, or

4.30)-Het, wherein Het is unsubstituted or substituted one, two or three times independently of each other by the groups a) to i) mentioned above, or

4.31)-Phenyl, wherein the phenyl ring is unsubstituted or substituted once, twice or three times by the following substituents:

4.31.1) halogen,

4.31.2)-(C ₁ -C ₆ )-alkyl,

4.31.3)-O-(C ₁ -C ₆ )-alkyl,

4.31.4) -S(O) ₂ -R16, wherein R16 is (C ₁ -C ₆ )-alkyl or -NH ₂ ,

5.-C(O)-N(R8)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or independently of each other mentioned above The radicals 4.1) to 4.31) or 4.8) a) to 4.8) i) are substituted once, twice or three times and R8 has the meanings stated above, or

6.-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het has the above-mentioned meanings and is unsubstituted or independently of each other by the above-mentioned groups Groups 4.1) to 4.31) or 4.8) a) to 4.8) i) are substituted once, twice or three times and R8 has the meanings stated above, or

7. -NH-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or substituted independently of one another by the abovementioned groups 4.1) to 4.30) or 4.8) a) to 4.8) i) once, twice or three times, or

8.-NH-Het, wherein Het has the above-mentioned meanings and is unsubstituted or substituted once independently of each other by the above-mentioned radicals 4.1) to 4.31) or 4.8)a) to 4.8)i), two or three times,

R3, R4, R5, R6 and R7 are identical or different and independently of each other are:

1. Hydrogen atom,

2. Halogen,

3. -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or three times by halogen,

4. -O-(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, or

5. -S-(C ₁ -C ₆ )-alkyl, or

R4 and R5 or R5 and R6 together with the carbon atoms to which they are attached in each case independently form a 5- or 6-membered ring which is aromatic or saturated and contains 0, 1 or 2 a heteroatom selected from oxygen, nitrogen or sulfur, wherein said ring is unsubstituted or substituted once or twice by halogen on one or several carbon atoms, other groups R3, R6 and R7 or R3, R4 and R7 have the meanings of 1. to 5. mentioned above.

For case b)

R1 is a hydrogen atom or -(C ₁ -C ₆ )-alkyl,

R2 is -(C ₁ -C ₆ )-alkyl, wherein the alkyl is substituted once, twice or three times by the following substituents:

1.-C(O)-O-R8', wherein R8' is

1.1) hydrogen atom or

1.2)-(C ₁ -C ₆ )-Alkyl,

2. -(C ₁ -C ₆ )-Alkyl-O-R8', wherein R8' has the meanings stated above,

3. -(C ₆ -C ₁₄ )-aryl, wherein aryl is substituted independently of one another once, twice or three times by the following substituents:

3.1) -(C ₂ -C ₆ )-alkyl-C(O)-O-R8', wherein R8' has the meanings stated above,

3.2) -O-(C ₁ -C ₆ )-alkyl-C(O)-O-R8', wherein R8' has the meanings stated above,

3.3)-N(R14)-(R15), wherein R14 and R15 form a 5-, 6- or 7-membered saturated ring together with the nitrogen atom to which they are attached, wherein the heteroatom selected from oxygen, sulfur and nitrogen is also One or two further carbon atoms may be substituted, in the case of nitrogen, the nitrogen atoms may independently of one another be unsubstituted or substituted by (C ₁ -C ₆ )-alkyl,

3.4) -(CH ₂ ) _k -N(R9')-(R10'), wherein k is 2, 3, 4 or 5, R9' and R10' are identical or different and independently of each other,

3.4.1) Hydrogen or

3.4.2) -(C ₁ -C ₆ )-alkyl, or

R9' and R10' form a 5-, 6- or 7-membered saturated ring together with the nitrogen atom to which they are attached, wherein heteroatoms selected from oxygen, sulfur and nitrogen can also replace one or two additional carbon atoms, in In the case of nitrogen, the nitrogen atoms can independently of one another be unsubstituted or substituted by (C ₁ -C ₆ )-alkyl,

3.5) -O-(C ₂ -C ₆ )-alkyl-N(R9')-R10', wherein R9' and R10' have the meanings stated above,

3.6) -N(R8')-C(O)-(C ₁ -C ₆ )-alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by the following substituents:

3.6.1) Halogen,

3.6.2) cyano group,

3.6.3) Nitro,

3.6.4) Hydroxyl,

3.6.5) amino group,

3.6.6)-C(O)-O-(C ₁ -C ₆ )-alkyl, or

3.6.7) -C(O)-OH, and R8' has the meanings stated above,

3.7) -Phenyl, wherein the phenyl ring is unsubstituted or substituted once, twice or three times by the following substituents:

3.7.1) Halogen,

3.7.2) -(C ₁ -C ₆ )-Alkyl,

3.7.3)-O-(C ₁ -C ₆ )-alkyl,

3.7.4) -S(O) ₂ -R16', wherein R16' is (C ₁ -C ₆ )-alkyl or -NH ₂ ,

4. Het, wherein Het is a saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring containing 1, 2 or 3 identical or different ring heteroatoms selected from nitrogen, oxygen and sulfur ring system, and is unsubstituted or substituted once, twice or three times with the following substituents:

4.1) Halogen,

4.2) cyano,

4.3) Nitro,

4.4) Hydroxyl,

4.5) amino group,

4.6)-C(O)-O(C ₁ -C ₆ )-alkyl,

4.7) -C(O)-OH,

4.8) -(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or substituted independently of each other once, twice or three times by halogen,

4.9) -O-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or substituted independently of each other once, twice or three times by halogen,

4.10) pyridyl, or

4.11) Phenyl, wherein phenyl is unsubstituted or substituted once independently of each other by a group selected from halogen, -(C ₁ -C ₆ )-alkoxy and -(C ₁ -C ₆ )-alkyl or more than once, and

R4 and R5 or R5 and R6 together with the carbon atoms to which they are attached in each case independently form a 5- or 6-membered ring which is saturated and contains one or two rings selected from oxygen, nitrogen or sulfur wherein said ring is unsubstituted or substituted once or twice by halogen on one or several carbon atoms, the other groups R3, R6 and R7 or R3, R4 and R7 are hydrogen, provided that Unsubstituted benzo[1,3]dioxole rings are excluded.

Michael Murray demonstrated that compounds containing unsubstituted benzo[1,3]dioxole as a group can inhibit cytochrome P450 liver enzymes (Michael Murray, Current Drug Metabolism 2000, 67-84). Said groups are believed to be responsible for these important toxicological effects. For this reason it is excluded from the compounds of formula I.

The present invention also relates to compounds of the following formula I, wherein

For case a),

R1 is a hydrogen atom or -(C ₁ -C ₆ )-alkyl,

R2 is -(C ₁ -C ₆ )-alkyl, wherein the alkyl is substituted once, twice or three times by the following substituents:

1.-(C ₁ -C ₆ )-alkyl-O-(C ₆ -C ₁₄ )-aryl,

2.-(C ₀ -C ₆ )-Alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkyl, wherein R8 is

i) a hydrogen atom,

ii) -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of each other once, twice or three times by the following substituents: -NH ₂ , -CN, OH, -C(O )-OH, -C(O)-OC ₁ -C ₆ )-alkyl, -C(O)-NH-OH, NO ₂

or halogen, or

iii) OH,

3.-C(O)-N(R9)-(R10), wherein R9 and R10 are identical or different and independently of each other:

i) a hydrogen atom or

ii) -(C ₁ -C ₆ )-alkyl, or

R9 and R10 form a 5-, 6- or 7-membered saturated ring together with the nitrogen atoms they are connected to, wherein heteroatoms selected from oxygen, sulfur and nitrogen can also replace one or two additional carbon atoms, in nitrogen In this case, the nitrogen atoms can independently of one another be unsubstituted or substituted by (C ₁ -C ₆ )-alkyl,

4. Phenyl, wherein phenyl is substituted one, two or three times independently of each other by the following substituents:

4.1)-(C ₀ -C ₆ )-Alkyl-C(O)-O-R8, wherein R8 has the meanings stated above,

4.2)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings stated above,

4.3)-(C ₀ -C ₆ )-Alkyl-C(O)-NH-CN,

4.4)-(C ₀ -C ₆ )-alkyl-C(O)-(C ₀ -C ₆ )-alkyl-Het, wherein Het is a group selected from the group consisting of azepine, azetidine alkanes, aziridines, benzimidazoles, benzofurans, benzo[1,4]dioxins, 1,3-benzodioxoles, 4H-benzo[1,4]oxanes Ozine, benzoxazole, benzothiazole, benzothiophene, quinazolidin, quinoline, quinoxaline, chroman, cinnoline, 1,2-diazepine, 1,3-di Azepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman , isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, ethylene oxide, piperazine, piperidine, Phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3- Thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1 , 2,3-triazole or 1,2,4-triazole, and wherein Het is unsubstituted or independently substituted once, twice or three times by the following substituents:

a) halogen,

b) cyano,

c) nitro,

d) hydroxyl,

e) amino groups,

f)-C(O)-O-(C ₁ -C ₆ )-alkyl,

g)-C(O)-OH,

h) -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or three times by halogen,

i) -O-(C ₁ -C ₆ )-alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen or -N(R9)-(R10),

j)-O,

k)-Het, wherein Het is as defined above,

l) -(C ₂ -C ₆ )-alkenyl, wherein alkenyl is unsubstituted or substituted once, twice or three times by halogen or -N(R9)-(R10), or

m)-(C ₂ -C ₆ )-alkynyl, wherein alkynyl is unsubstituted or substituted once, twice or three times by halogen or -N(R9)-(R10),

4.5)-(C ₀ -C ₆ )-Alkyl-C(O)-(C ₀ -C ₆ )-Alkyl-OH,

4.6)-O-(C ₀ -C ₆ )-alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings stated above,

4.7)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-N(R9)-(R10), wherein R8, R9 and R10 has the meaning stated above,

4.8) -(C ₀ -C ₄ )-Alkyl-N(R8)-S(O) ₂ -(C ₀ -C ₆ )-Alkyl-Het, wherein Het is as defined above and is unsubstituted or independently of each other by one, two or three substitutions by the groups a) to m) mentioned above and R8 has the meanings stated above,

4.9)-(C ₀ -C ₄ )-Alkyl-S(O) ₂ -(C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-Phenyl, wherein phenyl is unsubstituted or independently of each other one, two or three times by the groups a) to m) mentioned above,

4.10)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-Het, wherein R8 has the above-mentioned meanings, Het has the above-mentioned and are unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above,

4.11)-(C ₀ -C ₆ )-alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-phenyl, wherein phenyl is unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above,

4.12)-(C ₀ -C ₆ )-Alkyl-N(R9)-(R10), wherein R9 and R10 have the meanings stated above,

4.13) -(CH ₂ ) _y -N(R8)-C(O)-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or independently of each other by the groups mentioned above a) to m) substituted once, twice or three times and y is 1 or 2,

4.14)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-(C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-Phenyl, wherein phenyl is unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above,

4.15)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or independently of each other mentioned above The groups a) to m) are substituted once, twice or three times,

4.16)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or independently of each other by the above The groups a) to m) mentioned are substituted once, twice or thrice,

4.17)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkenyl, wherein alkenyl is unsubstituted or independently of each other Substituted once, twice or three times by the groups a) to m) mentioned above,

4.18)-(C ₀ -C ₄ )-alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-alkynyl, wherein the alkynyl is unsubstituted or independently of each other replaced by the above The groups a) to m) mentioned are substituted once, twice or thrice,

4.19)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-Phenyl, wherein benzene radicals are unsubstituted or substituted independently of each other once, twice or three times by the abovementioned groups a) to m),

4.20)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is as defined above and is unsubstituted or independently of each other one, two or three times by the groups a) to m) mentioned above,

4.21)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-(C ₀ -C ₆ )-Alkyl-N(R11)-R12, wherein R8 has the meanings described above , R11 and R12 are the same or different and independently of each other are:

4.21.1) Hydrogen atoms,

4.21.2)-(C ₁ -C ₆ )-Alkyl,

4.21.3)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-phenyl, wherein phenyl is unsubstituted or independently of one another by the groups a) to m) mentioned above instead of once, twice or thrice,

4.21.4)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is as defined above and is unsubstituted or substituted independently of each other by the groups a) to m) mentioned above once, twice once or three times,

4.21.5) -C(O)-(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or independently of one another by the groups a) to m) mentioned above three times,

4.21.6)-C(O)-(C ₃ -C ₆ )-cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted independently of one another once, twice once or three times,

4.21.7)-C(O)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-phenyl, wherein phenyl is unsubstituted or independently of each other by the above-mentioned groups a) to m) are substituted once, twice or three times,

4.21.8)-C(O)-(C ₀ -C ₆ )-alkyl-Het, wherein Het is as defined above and is unsubstituted or independently of each other by the above-mentioned groups a) to m ) instead of one, two or three times,

4.21.9) -SO ₂ -(C ₀ -C ₆ )-alkyl, wherein the alkyl groups are unsubstituted or substituted independently of one another once, twice or three times by the groups a) to m) mentioned above,

4.21.10) -NH-SO ₂ -(C ₀ -C ₆ )-alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or independently of one another by the groups a) to m) mentioned above three times,

4.21.11)-SO ₂ -(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-phenyl-(C ₀ -C ₆ )-alkyl, where the phenyl groups are unsubstituted or each other independently substituted one, two or three times by the groups a) to m) mentioned above,

4.21.12) -SO ₂ -(C ₀ -C ₆ )-alkyl-Het, wherein Het is as defined above and is unsubstituted or substituted independently of each other by the abovementioned groups a) to m) once, twice or three times,

4.22) -O-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is as defined above and is unsubstituted or substituted independently of each other by the groups a) to m) mentioned above once, twice once or three times,

4.23)-(C ₀ -C ₄ )-Alkyl-Het, wherein Het is as defined above and is unsubstituted or substituted independently of each other by the groups a) to m) mentioned above once, twice or three times,

5.-C(O)-N(R8)-(C ₀ -C ₆ )-alkyl-phenyl, wherein phenyl is unsubstituted or independently of each other by the above-mentioned groups 4.1) to 4.23) or 4.4) a) to 4.4) m) are substituted once, twice or three times and R8 has the meanings stated above, or

6. -C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is azepine, azetidine, aziridine, benzimidazole, benzo Furan, benzo[1,4]dioxin, 1,3-benzodioxole, 4H-benzo[1,4]oxazine, benzoxazole, benzothiazole, benzo Thiophene, quinazolidin, quinoline, quinoxaline, chroman, cinnoline, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxol, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazole, phenoline, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyran oxazine, pyridine, pyrimidine, pyridimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, sulfur Morpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4 - triazole, Het is unsubstituted or substituted independently of each other once, twice or three times by the abovementioned radicals 4.1) to 4.4) or 4.4) a) to 4.4) m) and R8 has the above-mentioned meanings ,

R3, R4, R5, R6 and R7 are the same or different and independently of each other,

1. Hydrogen atom,

2. Halogen,

3. -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, or

4. -O-(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, or

R4 and R5 or R5 and R6 together with the carbon atoms to which they are attached in each case independently form a dioxane, dioxole, dihydrofuran or furan ring, wherein said ring is unsubstituted or substituted once or twice by halogen on one or several carbon atoms, the other groups R3, R6 and R7 or R3, R4 and R7 have the meanings of 1. to 4. mentioned above,

or, for case b)

R1 is a hydrogen atom or -(C ₁ -C ₄ )-alkyl,

R2 is -(C ₁ -C ₄ )-alkyl, wherein the alkyl is substituted once, twice or three times by the following substituents:

1.-C(O)-O-R8', wherein R8' is

1.1) hydrogen atom or

1.2)-(C ₁ -C ₄ )-Alkyl,

2. -(C ₁ -C ₄ )-Alkyl-O-R8', wherein R8' has the meanings stated above,

3. Phenyl, wherein the phenyl groups are independently substituted one, two or three times by the following substituents:

3.1) -(C ₂ -C ₄ )-alkyl-C(O)-O-R8', wherein R8' has the meanings stated above,

3.2) -O-(C ₁ -C ₄ )-alkyl-C(O)-O-R8', wherein R8' has the meanings stated above,

3.3) -N(R14)-(R15), wherein R14 and R15 together with the nitrogen atom to which they are attached form a group derivable from: pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazole Alkane, piperazine, isoxazolidine, morpholine, isothiazolidine or thiomorpholine, in the case of nitrogen, the nitrogen atoms can independently of one another be unsubstituted or be replaced by (C ₁ -C ₄ )-alkyl replaced by

3.4) -(CH ₂ ) _k -N(R9')-(R10'), wherein k is 2, 3, 4 or 5, R9' and R10' are identical or different and independently of each other are:

3.4.1) A hydrogen atom or

3.4.2) -(C ₁ -C ₆ )-alkyl, or

R9' and R10' together with the nitrogen atom to which they are attached form a group derived from: pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, methazolidine phenoline, isothiazolidine or thiomorpholine, in the case of nitrogen, the nitrogen atoms may independently of one another be unsubstituted or substituted by (C ₁ -C ₄ )-alkyl,

3.5) -O-(C ₂ -C ₆ )-alkyl-N(R9')-R10', wherein R9' and R10' have the meanings stated above,

3.6) -N(R8')-C(O)-(C ₁ -C ₆ )-alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by the following substituents:

3.6.1) Halogen,

3.6.2) cyano group,

3.6.3) Nitro,

3.6.4) Hydroxyl,

3.6.5) amino group,

3.6.7)-C(O)-O-(C ₁ -C ₆ )-alkyl, or

3.6.8) -C(O)-OH, and R8' has the meanings stated above,

3.7) -Phenyl, wherein the phenyl ring is unsubstituted or substituted once, twice or three times by the following substituents:

3.7.1) Halogen,

3.7.2) -(C ₁ -C ₆ )-Alkyl,

3.7.3) -O-(C ₁ -C ₆ )-alkyl, or

3.7.4) -S(O) ₂ -R16', wherein R16' is (C ₁ -C ₆ )-alkyl or -NH ₂ ,

4. Het, wherein Het is azepine, azetidine, aziridine, benzimidazole, benzofuran, benzo[1,4]dioxin, 1,3-benzodiox Heterocyclopentene, 4H-benzo[1,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazolidine, quinoline, quinoxaline, chroman, cinnoline , 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole , indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine , oxazole, ethylene oxide, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine , tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3, 5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4-triazole, and Het is unsubstituted or substituted once, twice independently of each other by the following substituents times or times:

4.1) Halogen,

4.2) cyano,

4.3) Nitro,

4.4) Hydroxyl,

4.5) amino group,

4.6)-C(O)-O(C ₁ -C ₆ )-alkyl,

4.7) -C(O)-OH,

4.8) -(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or substituted independently of each other once, twice or three times by halogen,

4.9) -O-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or substituted independently of each other once, twice or three times by halogen,

4.10) pyridyl, or

4.11) Phenyl, wherein phenyl is unsubstituted or substituted one, two or three times independently of each other by groups selected from the group consisting of halogen, -(C ₁ -C ₆ )-alkoxy and -(C ₁ -C ₆ )-alkyl, and

R4 and R5 or R5 and R6 together with the benzene ring and the carbon atom to which they are attached in each case independently form a ring system selected from the group consisting of: benzo[1,4]dioxane, 2,3-dihydro Benzofuran and 2,2-difluorobenzo[1,3]dioxole, the other groups R3, R6 and R7 or R3, R4 and R7 are hydrogen atoms.

The present invention also relates to compounds of the following formula I, wherein, for the case of a),

R1 is a hydrogen atom,

R2 is -(C ₁ -C ₃ )-alkyl, wherein the alkyl is substituted by the following substituents:

1. Phenyl, wherein phenyl is substituted one, two or three times independently of each other by the following substituents:

1.1) _-CH2 -C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl, propyl or butyl,

1.2)-(C ₀ -C ₆ )-alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 are hydrogen atoms, methyl, ethyl, propyl or butyl, or

R9 and R10 together with the nitrogen atom to which they are attached form a group derived from: pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, morpholine, Isothiazolidines or thiomorpholines, in the case of nitrogen, the nitrogen atoms may independently of one another be unsubstituted or substituted by (C ₁ -C ₄ )-alkyl,

1.3)-(C ₀ -C ₄ )-Alkyl-C(O)-NH-CN,

1.4)-O-(C ₀ -C ₆ )-alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings mentioned in 1.2) above,

1.5)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-N(R9)-(R10), wherein R8, R9 and R10 has the meaning stated above,

1.6)-C(O)-N(R8)-(C ₀ -C ₂ )-Alkyl-Het, wherein R8 has the meanings stated above and Het is azepine, azetidine, azetidine Propane, benzimidazole, benzofuran, benzo[1,4]dioxin, 1,3-benzodioxole, 4H-benzo[1,4]oxazine, benzox Azole, benzothiazole, benzothiophene, quinazolidine, quinoline, quinoxaline, chroman, cinnoline, 1,2-diazepine, 1,3-diazepine, 1 , 4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, Isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, ethylene oxide, piperazine, piperidine, phthalazine, pyran , pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1, 4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3- Triazole or 1,2,4-triazole and Het are unsubstituted or substituted one, two or three times independently of each other by the following substituents:

a) halogen,

b) cyano,

c) nitro,

d) hydroxyl,

e) amino groups,

f)-C(O)-O-(C ₁ -C ₄ )-alkyl,

g)-C(O)-OH,

h) -(C ₁ -C ₄ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or three times by halogen,

i) -O-(C ₁ -C ₄ )-Alkyl, wherein the alkyl group is unsubstituted or substituted once, twice or three times by halogen, or

1.7)-C(O)-N(R8)-(C ₀ -C ₄ )-alkyl-phenyl, wherein phenyl is unsubstituted or independently of one another by the groups a) to i) mentioned above instead of once, twice or thrice,

1.8) -CH ₂ -N(R9)-(R10), wherein R9 and R10 have the meanings stated above,

1.9) -(CH ₂ ) _y -N(R8)-C(O)-(C ₁ -C ₄ )-Alkyl, wherein the alkyl groups are unsubstituted or independently of one another by the groups mentioned above a) to i) substitution once, twice or three times and y is 1 or 2,

1.10) -(CH ₂ ) _x -N(R8)-C(O)-(C ₀ -C ₂ )-alkyl-phenyl, wherein phenyl is unsubstituted or independently of each other by the above-mentioned groups Groups a) to i) are substituted once, twice or three times and x is 0, 1 or 2,

1.11) -(CH ₂ ) _x -N(R8)-C(O)-(C ₀ -C ₂ )-alkyl-Het, wherein Het is unsubstituted or independently of each other by the above-mentioned groups a ) to i) are substituted once, twice or three times and x is 0, 1 or 2,

1.12) -(CH ₂ ) _x -N(R8)-C(O)-O-(C ₁ -C ₄ )-Alkyl, wherein the alkyl group is unsubstituted or independently of each other by the groups mentioned above a) to i) are substituted once, twice or three times and x is 0, 1 or 2,

1.13) -(CH ₂ ) _x -N(R8)-C(O)-O-(C ₀ -C ₄ )-alkyl-phenyl, wherein phenyl is unsubstituted or independently of each other mentioned above The groups a) to i) of are substituted once, twice or three times and x is 0, 1 or 2,

1.14) -(CH ₂ ) _x -N(R8)-C(O)-O-(C ₀ -C ₄ )-alkyl-Het, wherein Het is unsubstituted or independently of each other by the above-mentioned groups Groups a) to i) are substituted once, twice or three times and x is 0, 1 or 2,

1.15)-( _CH2 ) _x -N(R8)-C(O)-N(R11)-R12, wherein R8 and x have the meanings stated above, R11 and R12 are identical or different and independently of each other:

1.15.1) a hydrogen atom,

1.15.2) methyl, ethyl, propyl or butyl,

1.15.3) -(C ₀ -C ₂ )-alkyl-phenyl, wherein phenyl is unsubstituted or substituted independently of one another once, twice or three times by the groups a) to i) mentioned above,

1.15.4)-(C ₀ -C ₂ )-Alkyl-Het, wherein Het is unsubstituted or substituted independently of each other once, twice or three times by the groups a) to i) mentioned above,

1.15.5)-C(O)-(C ₁ -C ₄ )-alkyl,

1.15.6)-C(O)-(C ₀ -C ₂ )-alkyl-phenyl,

1.15.7)-C(O)-(C ₀ -C ₂ )-alkyl-Het,

1.15.8) -SO ₂ -(C ₁ -C ₄ )-alkyl,

1.15.9) -SO ₂ -(C ₀ -C ₄ )-alkyl-phenyl, or

1.15.10) -SO ₂ -(C ₀ -C ₂ )-alkyl-Het,

R3, R4, R5, R6 and R7 are identical or different and independently of each other are:

1. Hydrogen atom,

2. Halogen,

3. -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or three times by halogen,

4. -O-(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of each other by halogen once, twice or three times, or

R4 and R5 or R5 and R6 together with the carbon atoms they are connected to independently form dioxane, dioxole, dihydrofuran or furan ring, other groups R3, R6 and R7 or R3, R4 and R7 have the meanings of 1 to 4 mentioned above,

Or, for case b),

R1 is a hydrogen atom,

R2 is -(C ₁ -C ₂ )-alkyl, wherein the alkyl is substituted once, twice or three times by the following substituents:

1.-C(O)-O-R8', wherein R8' is

1.1) hydrogen atom or

1.2) -(C ₁ -C ₂ )-Alkyl,

2. Phenyl, wherein phenyl is substituted one, two or three times independently of each other by the following substituents:

2.1) -O-(C ₂ -C ₄ )-Alkyl-N(R9')-R10', wherein R9' and R10' are independently hydrogen atom, methyl or ethyl, or R9' and R10' Together with the nitrogen atom to which they are attached, form a group derivable from pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, in the case of piperazine the second nitrogen atom can be replaced by methyl or ethyl base substitution,

2.2) -O-(C ₁ -C ₂ )-alkyl-C(O)-O-R8', wherein R8' are independently of each other a hydrogen atom, methyl or ethyl, or

2.3) -N(R14)-(R15), wherein R14 and R15 together with the nitrogen atom to which they are attached form a group derivable from: pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazole Alkane, piperazine, isoxazolidine, morpholine, isothiazolidine or thiomorpholine, in the case of nitrogen, the nitrogen atoms may independently of one another be unsubstituted or substituted by methyl or ethyl,

2.4) -(CH ₂ ) _k -N(R9')-(R10'), wherein k is 2, 3 or 4, R9' and R10' are the same or different and independently of each other a hydrogen atom, methyl or ethyl ,or

R9' and R10' together with the nitrogen atom to which they are attached form a group derivable from pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, in the case of piperazine the second nitrogen atom can be is substituted by methyl or ethyl, and R4 and R5 or R5 and R6 together with the benzene ring and the carbon atom to which they are attached in each case independently form each other a ring system selected from the group consisting of: benzo[1,4]di Oxane, 2,3-dihydrobenzofuran and 2,2-difluorobenzo[1,3]dioxole, other groups R3, R6 and R7 or R3, R4 and R7 are hydrogen atom.

The invention also relates to compounds of formula I, such as:

Pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-(4-propylcarbamoylbenzylamide),

Pyrimidine-4,6-carboxylic acid 4-(4-isopropylcarbamoylbenzylamide) 6-(3-methoxybenzylamide),

[4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoisopropyl ester,

Pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-[(2-phenoxy-ethyl)amide],

(5-{[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}pentyl)carboxyaminomethyl ester,

Pyrimidine-4,6-carboxylic acid 4-[4-(2-dimethylaminoethylcarbamoyl)benzylamide]6-(3-methoxybenzylamide),

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[4-(2-dimethylaminoethyl Carbamoyl) benzylamide],

Pyrimidine-4,6-carboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-dimethylaminoethylcarbamoyl)benzylamide],

Pyrimidine-4,6-carboxylic acid 4-dimethylcarbamoylmethylamide 6-(3-methoxybenzylamide),

[4-({[6-(3-aminobenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyamino tert-butyl ester,

Pyrimidine-4,6-dicarboxylic acid 4-(3-chlorobenzylamide) 6-(4-fluoro-3-methylbenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-[(2-chloropyridin-4-ylmethyl)amide] 6-(4-fluoro-3-methylbenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-benzylamide 6-(4-fluoro-3-methylbenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[(pyridin-4-ylmethyl)amide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-(pyridin-3-ylmethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl] benzylamide},

Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-yl-2-oxoethoxy)benzylamide],

Pyrimidine-4,6-carboxylic acid 4-(4-diethylcarbamoylmethoxybenzylamide) 6-(4-fluoro-3-methylbenzylamide),

Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(isopropylcarbamoylmethyl)benzylamide],

Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[(2-morpholin-4-ylethylcarbamoyl)methyl]benzylamide} ,

Pyrimidine-4,6-carboxylic acid 4-(4-diethylcarbamoylmethylbenzylamide) 6-(4-fluoro-3-methylbenzylamide),

Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-yl-2-oxoethyl)benzylamide],

Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(isopropylcarbamoylmethoxy)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[(pyridin-3-ylmethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-({[(pyridin-4-ylmethyl)carbamoyl]methyl}amide),

Pyrimidine-4,6-carboxylic acid 4-({[(2-chloropyridin-4-ylmethyl)carbamoyl]methyl}amide) 6-(3-methoxybenzylamide),

Pyrimidine-4,6-carboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-({[(2-chloropyridin-4-ylmethyl)carbamoyl]methyl}amide),

[4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoisobutyl ester,

[4-({[6-(3-Methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoethyl ester,

[4-({[6-(3-Methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoallyl ester,

Pyrimidine-4,6-carboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(1-methylpiperidin-3-yloxy)benzylamide],

Pyrimidine-4,6-carboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-({[(pyridin-3-ylmethyl)carbamoyl]methyl}amide),

Pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

Pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)benzylamide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[(2′-sulfamoyldiphenyl- 2-ylmethyl) amides],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(thiophen-2-ylmethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(5-methylfuran-2-ylmethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(5-methylfuran-2-ylmethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(5-pyridin-2-ylthiophen-2-ylmethyl)amide] ,

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(pyridin-3-ylmethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[(pyridin-3-ylmethyl)amide] ,

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[(5-methylfuran-2-ylmethyl) base) amides],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[(thiophen-2-ylmethyl)amide] ,

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(5-methylisoxazol-3-ylmethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(1-methyl-1H-pyrazol-4-ylmethyl)amide ],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(2,5-dimethylfuran-3-ylmethyl)amide] ,

Pyrimidine-4,6-carboxylic acid 4-[(6-aminopyridin-3-ylmethyl)amide] 6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(1-methyl-1H-pyrrol-2-ylmethyl)amide] ,

Pyrimidine-4,6-carboxylic acid 4-[(1H-benzimidazol-2-ylmethyl)amide]6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[(pyrazin-2-ylmethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-[(2,2-difluorobenzo[1,3]dioxol-5-ylmethyl)amide]6-[(pyridin-4-ylmethyl) base) amides],

Methyl ({6-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)carbamoyl]pyrimidine-4-carbonyl}amino)acetate,

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(2-methyl-1H-imidazol-4-ylmethyl)amide] ,

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[(2-pyridin-2-ylethyl)amide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-{[3-(4-fluorophenyl)-1H-pyrazole-4- base methyl] amides},

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[4-(3-dimethylaminopropoxy base) benzylamide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[4-(2-dimethylaminoethoxy base) benzylamide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[3-(2-dimethylaminoethoxy base) benzylamide],

Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[(pyridin-4-ylmethyl)amide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-(4-[3′-methylsulfonyl]ureidobenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzyl aride)6-[4-(4-oxopiperidine-1-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(4-oxopiperidine-1-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(4-oxopiperidine-1-carbonyl)benzylamide ],

Pyrimidine-4,6-dicarboxylic acid 4-[4-(4-hydroxypiperidine-1-carbonyl)benzylamide]6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(4-hydroxypiperidine-1-carbonyl)benzylamide] ,

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(4-hydroxypiperidine-1-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(thiomorpholine-4-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(3-oxopiperazine-1-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(3-oxopiperazine-1-carbonyl)benzylamide ],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(3-oxopiperazine-1-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(2-hydroxyethylcarbamoyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-hydroxyethylcarbamoyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide},

Pyrimidine-4,6-dicarboxylic acid 4-(4-cyanocarbamoylbenzylamide) 6-(4-fluoro-3-methylbenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(3-morpholin-4-ylpropylcarbamoyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(3-morpholin-4-yl-propylcarbamoyl ) benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(4-methylpiperazine-1-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-{4-[(pyridin-4-ylmethyl)carbamoyl]benzyl base amides},

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-(4-[3′-methylsulfonyl]ureidobenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-(4-[3-methylsulfonyl]ureidobenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-(3-[3′-methylsulfonyl]ureidobenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(4-hydroxycarbamoylbenzylamide) 6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(hydroxycarbamoylmethylcarbamoyl)benzylamide] ,

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(1-methylpiperidin-3-yloxy)benzyl base amides],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-piperazin-1-ylethylcarbamoyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-(4-hydroxycarbamoylbenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-(4-hydroxycarbamoylbenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(1-methylpiperidin-3-yloxy)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-tert-butylcarbamoylbenzylamide) 6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[methyl-(1-methylpiperidin-4-yl)carbamoyl]benzylamide},

{4-[({6-[(2,3-Dihydrobenzofuran-5-ylmethyl)carbamoyl]pyrimidine-4-carbonyl}amino)methyl]benzoylamino}acetic acid,

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-{4-[4-(2-dimethylaminoethyl)piperazine-1-carbonyl]benzylamide}6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-(4-[3′-methylsulfonyl]ureidobenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[3-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

[4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)benzoylamino]acetic acid,

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-piperazin-1-ylacetylamino)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-yl-ethylcarbamoyl)benzylamide],

Methyl [4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)benzoylamino]acetate,

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[3-(morpholine-4-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[(piperidin-4-ylmethyl)carbamoyl]benzylamide},

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(piperidin-4-ylcarbamoyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(piperidin-4-ylcarbamoyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[methyl-(1-methylpiperidin-4-yl)carbamoyl]benzyl amides},

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine -7-ylmethyl)amide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[(piperidin-4-ylmethyl)carbamoyl]benzylamide},

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(4-methylpiperazine-1-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(4-pyridin-4-ylpiperazine-1-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-morpholin-4-ylacetylamino)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(morpholine-4-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-(4-[p-toluenesulfonyl]ureidobenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(4-methylpiperazine-1-carbonyl)benzylamide ],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl ) benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-(4-[3′-phenylsulfonyl]ureidobenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(2-morpholin-4-yl-ethylcarbamoyl ) benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(2-pyrrolidin-1-ylethoxy)benzyl amides],

Pyrimidine-4,6-dicarboxylic acid 4-[4-(3-cyclohexanecarbonylureido)benzylamide]6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[3-(pyridine-3-carbonyl)ureido]benzylamide},

Pyrimidine-4,6-dicarboxylic acid 4-[4-(3-isobutyrylureido)benzylamide]6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-pyrrolidin-1-ylacetylamino)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-[(4-chlorothiophen-2-ylmethyl)amide]6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[2-(2-oxopyrrolidin-1-yl)acetylamino]benzylamide},

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(thiophen-3-ylmethyl)amide],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(3-methylthiophen-2-ylmethyl)amide],

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(5-methylthiophen-2-ylmethyl)amide],

Pyrimidine-4,6-dicarboxylic acid 4-[4-(2-dimethylaminoacetylamino)benzylamide]6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(2-morpholin-4-ylethoxy)benzyl amides],

Pyrimidine-4,6-dicarboxylic acid 4-[4-(3-cyclohexylureido)benzylamide]6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-{4-[3-(2,6-dichloropyridin-4-yl)ureido]benzylamide} 6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-[4-(3-tert-butylureido)benzylamide]6-(3-methoxybenzylamide),

[4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminobut-2-ynyl ester,

Pyrimidine-4,6-dicarboxylic acid 4-(4-ethanesulfonylaminobenzylamide) 6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(thiophene-2-sulfonylamino)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2,2,2-trifluoroethanesulfonylamino)benzylamide],

[4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminomethyl ester,

[4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoprop-2-ynyl ester,

[4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyamino 2-methoxyethyl ester,

[4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyamino 4-fluorophenyl ester,

Pyrimidine-4,6-dicarboxylic acid 4-[4-(3-benzoylureido)benzylamide]6-(3-methoxybenzylamide),

[3-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminobut-2-ynyl ester,

[3-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoprop-2-ynyl ester,

[3-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoisopropyl ester,

Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-pyrrolidin-1-ylethylcarbamoyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide},

Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-(4-diethylcarbamoylbenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-{4-[2-(2,6-dimethylpiperidin-1-yl)-2-oxoethyl]benzylamide}6-(4-fluoro- 3-methylbenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(1-methylpiperidin-3-yloxy)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methoxybenzylamide),

Pyrimidine-4,6-dicarboxylic acid 4-[(2-chloropyridin-4-ylmethyl)amide]6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide],

Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-(4-methanesulfonylaminobenzylamide) or

Pyrimidine-4,6-dicarboxylic acid 4-(4-methanesulfonylbenzylamide) 6-(3-methoxybenzylamide).

The present invention also relates to compounds of formula I

and/or all stereoisomeric forms of the compound of formula I and/or mixtures of these forms in any proportion and/or physiologically tolerable salts of the compound of formula I in the preparation for the prophylaxis and treatment in which matrix metals are involved Use in medicine for diseases in which protease 13 activity is increased.

The term "halogen" is understood to mean fluorine, chlorine, bromine or iodine.

The term "alkyl" is to be understood in the broadest possible sense as meaning a hydrocarbon group whose carbon chain is straight or branched, or consisting of a cyclic hydrocarbon group or a combination of straight and cyclic groups. Examples of straight and branched chain hydrocarbon groups are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl or hexyl, while cyclic groups can be cyclopropyl, cyclobutyl, cyclo Pentyl or cyclohexyl, the combination of linear and cyclic groups can be cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl. However, alkyl can also be mono- or polyunsaturated, for example (C ₂ -C ₆ )-alkenyl, for example ethene, propene, butene, methylpropene, isobutene, 1,3-butadiene or 1 , 3-pentadiene, or (C ₂ -C ₆ )-alkynyl, such as acetylene, propyne, butyne, 2-methyl-3-hexyne, 1,4-pentadiyne or 2-hex En-4-yne. The term "-(C ₀ -C ₆ )-alkyl" can be understood as referring to a hydrocarbon group whose carbon chain is straight or branched and contains 1 to 6 carbon atoms, such as methyl, ethyl, propyl, Isopropyl, butyl, tert-butyl, pentyl or hexyl. "-C ₀ -alkyl" is a covalent bond.

The term "-(C ₆ -C ₁₄ )-aryl" is understood to mean an aromatic carbon group having 6 to 14 carbon atoms in the ring. Examples of -(C ₆ -C ₁₄ )-aryl are phenyl, naphthyl such as 1-naphthyl and 2-naphthyl, biphenyl such as 2-biphenyl, 3-biphenyl and 4-biphenyl Phenyl, anthracenyl and fluorenyl. Biphenyl, naphthyl and especially phenyl are preferred aryl groups.

The term "R4 and R5 or R5 and R6 together with the carbon atoms to which they are attached in each case independently form a 5- or 6-membered ring which is aromatic or saturated and contains 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur" is understood to mean a ring system derived from: dioxole, pyrrole, pyrrolidine, pyridine, piperidine, dioxane, tetrahydro Pyridine, pyrazole, micon, pyrazoline, imidazoline, pyrazolidine, imidazolidine, pyridazine, pyrimidine, pyrazine, piperazine, pyran, furan, dihydrofuran, tetrahydrofuran, oxazole, isoxazole , 2-isoxazoline, isoxazolidine, morpholine, oxathiolane, thiopyran, thiazole, isothiazole, 2-isothiazoline, isothiazolidine or thiomorpholine.

The term "Het" can be understood as meaning a saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms. In the following monocyclic or bicyclic heterocyclic ring systems, Het contains 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. Monocyclic ring systems may be 3-, 4-, 5-, 6- or 7-membered rings. In bicyclic Het, two rings may be attached to each other, one of which may be a 5- or 6-membered heterocycle and the other may be a 5- or 6-membered heterocycle or a carbocycle. A bicyclic Het group may consist of, for example, 8, 9 or 10 ring atoms. Het includes saturated heterocyclic ring systems that do not have any double bonds in the ring as well as unsaturated heterocyclic ring systems, including monounsaturated and polysaturated heterocyclic ring systems, which have one or Multiple double bonds and form a stable ring system. Unsaturated rings can be partially unsaturated or form an aromatic system. The Het group contains the same or different heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocycles from which the Het group may be derived are acridinyl, aziocinyl, benzimidazolyl, benzofuryl, benzothiopyryl, benzothiophene, benzoxazolyl, benzo Thiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolidinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, benzo Dihydropyranyl, benzopyranyl, cinnolinyl, decahydroquinolyl, 2H-6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, Furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolyl, indolyl, 3H-indolyl, isobenzofuryl, Isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, Naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1 , 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazine Base, 2,3-diazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazine Base, pyridoxazole, pyridimidazole, pyridothiazole, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H -Quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3- Thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl and xanthyl.

Preferred are azepine, azetidine, aziridine, benzimidazole, benzofuran, benzo[1,4]dioxin, 1,3-benzodioxole, 4H -Benzo[1,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazolidine, quinoline, quinoxaline, chroman, cinnoline, 1,2-di Azepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinone morpholine, isochroman, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, epoxy Ethane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1, 2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1 , 2,4-triazine, 1,2,3-triazole or 1,2,4-triazole, etc., are also preferably formed from the listed heterocyclic rings by linking or fused to carbocyclic rings For example, benzo-fused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivatives of these heterocycles. Suitable nitrogen heterocycles can also exist in the form of N-oxides or quaternary salts, in which suitable nitrogen atoms are alkylated with (C ₁ -C ₄ )-alkyl groups. The Het group can be unsubstituted or substituted according to the listed definitions.

The term "R9 and R10 or R14 and R15 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, wherein a heteroatom selected from oxygen, sulfur and nitrogen may also replace one or two other The carbon atom of " can be understood as referring to the group that can be derived from the following: imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine.

Compounds of formula I can be obtained, for example, by compounding compounds of formula II

a) react with formula IIIa or IIIb compound to prepare

wherein R1, R2, R3, R4, R5, R6 and R7 have the meanings given in formula I and Y is halogen, hydroxyl or _C1 - _C4 -alkoxy, or together with carbonyl forms active esters or mixed anhydrides, To form a compound of formula I, if desired, the reaction product can be converted into its physiologically tolerable salt, or

b) reacting the compound of formula II with the compound of formula IIIa or IIIb to obtain the compound of formula IVa or IVb

wherein R1 to R7 have the meanings given in formula I and Y is halogen, hydroxy or _C1 - _C4 -alkoxy, or together with a carbonyl group forms active esters or mixed anhydrides, where necessary, the compound of formula IVa or IVb is purified, Compounds of formula Ilia or IIIb are then used to convert to compounds of formula I.

The preparation of the compounds of formula I and the preparation of the starting materials required for this purpose (when such materials are not commercially available) are described in more detail below.

The compounds of the present invention are most easily prepared by mixing the two components, the pyrimidine derivative of formula (II) and the amine of formula IIIa or IIIb, in equimolar amounts, and then mixing them at -30°C to 150°C , preferably at a temperature of 20° C. to 100° C. to obtain a compound of formula IVa or IVb, which is then reacted in a similar manner with an amine of formula IIIb or IIIa in a similar manner. The endpoint of the reaction can be determined, for example, by thin layer chromatography or HPLC-MS. Variations of this method include in suitable solvents such as diethyl ether, dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons such as dichloromethane, chloroform, trichloroethylene or tetrachloroethylene, benzene or toluene or polar solvents such as The reaction is carried out in dimethylformamide, acetone or dimethylsulfoxide. In this case, the reaction temperature is between room temperature and the boiling point of the solvent, particularly preferably the reaction temperature is between room temperature and 130°C.

The reaction can also be carried out via mixed anhydrides such as ethyl chloroformate or via active esters such as p-nitrophenyl esters (Y=ClCH ₂ -COO or NO ₂ -C ₆ H ₄ -O). Suitable methods are known and described in the literature.

If Y is OH, the compound of formula II or the compound of formula IVa or IVb can also be reacted with the amine of formula IIIa or IIIb, using conventional coupling reagents to activate the corresponding carboxylic acid in situ. Examples of these coupling agents are carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DCI) or N,N'-carbonyldiazoles such as N,N'-carbonyl Diimidazole or urea salts such as O-((cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) or O-(7 -Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). Suitable methods are known.

If amines of formula IIIa or IIIb are not commercially available, they can be prepared from appropriate commercially available starting compounds by methods known in the literature. Examples of suitable starter compounds for amines are nitriles, nitro compounds, formamides, carboxylates, carboxylic acids, aldehydes and bromides. Nitriles, nitro compounds and formamides can be reduced to amines by known methods. Carboxylic acids and carboxylic acid esters can be converted to formamides. Aldehydes can be directly converted to amines by reductive amination using _NH4Ac / _NaBH4 , or first converted to oximes and then reduced to amines using hydroxylamine.

The reaction can also be carried out in the presence of a base, if desired. Examples of bases suitable for addition are carbonates or bicarbonates such as sodium or potassium carbonate or sodium or potassium bicarbonate or tertiary amines such as triethylamine, tetrabutylammonium or ethyldiisopropylamine Or heterocyclic amines such as N-alkylmorpholines, pyridines or quinolines or dialkylanilines.

The product, especially the compound of formula IVa or IVb, can be purified, for example, by extraction or chromatography, for example on silica gel, if desired. The isolated product is recrystallized and, where appropriate, reacted with a suitable acid to obtain a physiologically tolerable salt. Examples of suitable acids are mineral acids such as hydrochloric and hydrobromic acids and sulfuric, phosphoric, nitric and perchloric acids, or organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, Citric acid, maleic acid, fumaric acid, phenylacetic acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid, oxalic acid, 4-aminobenzoic acid, naphthalene-1,5-disulfonic acid or ascorbic acid.

When starting compounds are not commercially available, starting compounds of formula IIIa or IIIb can be conveniently synthesized (e.g. Organikum, Organisch Chemisches Grundpraktikum [Organicum, basic practical course in organic chemistry], 15th edition, VEBDeutscher Verlag der Wissenschaften, 1976; An overview of the different possibilities can be found on page 822 in the Methods Index).

The starting compound of formula (II) can be obtained, for example, by utilizing methods known in the literature to convert pyrimidine-4,6-dicarboxylic acid into the corresponding pyrimidine-4, preferably in the presence of a catalyst such as dimethylformamide, 6-Dicarbonyl halide, preferably dicarbonyl chloride. The acid halide is then reacted, for example, either with a suitable alcohol such as p-nitrobenzyl alcohol to give the corresponding reactive ester, or with a lower alcohol such as methanol or ethanol to give the corresponding ester. It is also possible to first convert pyrimidine-4,6-dicarboxylic acid into a mixed anhydride in the presence of added suitable carboxylic acid or carboxylic acid ester such as ethyl chloroformate, which is then combined with an amine of formula IIIa or IIIb and IVa or IVb reaction to obtain the product of the present invention. Suitable methods are likewise described in the literature.

Pyrimidine-4,6-dicarboxylic acid can be obtained by methods known in the literature, for example by oxidation of 4,6-dimethylpyrimidine, which itself can be obtained, for example, by catalytic hydrogenation of commercially available 2-mercapto-4, 6-dimethylpyrimidine to get.

When the compounds of formula I permit diastereomeric or enantiomeric forms and are obtained in the form of their mixtures in selected syntheses, either by chromatography on optional chiral carrier substances or by fractional crystallization The diastereomeric salts formed by optically active bases or acids as auxiliary substances separate them into the pure stereoisomers, provided that the racemic compounds of the formula I are capable of being salified. For thin-layer or column chromatographic separation of optical antipodes, examples of suitable chiral stationary phases are modified silica supports (referred to as Pirkle phases) and high molecular weight carbohydrates such as triacetylcellulose. Gas chromatography on chiral stationary phases can also be used for analytical purposes after appropriate derivatization known to the person skilled in the art. For separation of the enantiomers of racemic carboxylic acids, commonly available optically active bases such as (-)-nicotine, (+)- and (-)-phenylethylamine, quinine, L-lysine amino acid or L- and D-arginine to form diastereomeric salts with different solubilities, the less soluble component is isolated as a solid, the more soluble diastereomer is isolated from the mother liquor, and the pure The enantiomers were isolated from the diastereomeric salts obtained according to this method. Racemic compounds of formula I containing basic groups such as amino groups are treated with optically active acids such as camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L-lactic acid and (+) and (-)- Mandelic acid is converted into the pure optical antipodes in the same way in principle. Chiral compounds containing alcohol or amine functions can also be converted into the corresponding esters or amides using appropriately activated or optionally N-protected enantiomerically pure amino acids, or conversely by converting chiral carboxylic acids with carboxyl-protected Enantiomerically pure amino acids are converted to amides, or enantiomerically pure hydroxycarboxylic acids such as lactic acid are used to convert to the corresponding chiral esters. The isomers can then be separated by existing diastereomers by virtue of the chirality of the amino acid or alcohol group which has been introduced into the enantiomerically pure form, by crystallization or chromatography on a suitable stationary phase, The entrained chiral molecular moieties are then removed again using an appropriate method.

The acidic or basic products of the compounds of formula I may exist in the form of their salts or in free form. Preference is given to pharmacologically tolerable salts such as alkali metal or alkaline earth metal salts or hydrochlorides, hydrobromic acid, sulfates, hemisulfates, all possible phosphates and salts of amino acids, natural bases or carboxylic acids .

Physiologically tolerable salts may be prepared in a manner known in the art from compounds of formula I which are capable of forming salts, including their stereoisomeric forms. Carboxylic acids with basic agents such as hydroxides, carbonates, bicarbonates, alkoxides and ammonia or organic bases such as trimethylamine, triethylamine, ethanolamine or triethanolamine or basic amino acids such as lysine, Ornithine or arginine form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts. When the compounds of the formula I have basic groups, suitable acid addition salts can also be prepared with strong acids. Organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclamate, trifluoromethanesulfonic acid, acetic acid , oxalic, tartaric, succinic and trifluoroacetic acids are suitable for this purpose.

As a result of their pharmacological properties, the compounds of formula I are suitable for the prophylaxis and treatment of all diseases in the course of which an increased activity of matrix metalloproteinase 13 is involved.

These diseases include degenerative joint diseases such as osteoarthrosis, spondylosis, or cartilage loss after relatively prolonged arthrodesis following joint trauma or meniscal injury or kneecap injury or ligament rupture. They also include diseases of connective tissue such as collagen diseases, periodontal diseases, wound healing disorders and chronic diseases of the locomotor organs such as inflammation, immunologically or metabolically determined acute and chronic arthritis, arthropathy, myalgia and bone metabolism Disorders or cancer diseases such as breast cancer.

The drug of the present invention can be administered by subcutaneous, intra-articular, intraperitoneal or intravenous injection. Intra-articular injections are preferred. Rectal, oral, inhalational or transdermal administration is also possible.

The invention also relates to processes for the preparation of medicaments in which at least one compound of the formula I is formulated together with pharmaceutically suitable and physiologically tolerable carriers and, where appropriate, other suitable active compounds, additives or auxiliary substances appropriate dosage form.

Compounds of formula I are mixed with additives suitable for the purpose, such as carrier substances, stabilizers or inert diluents, and then formulated into suitable administration forms such as tablets, sugar-coated tablets, hard gelatin capsules, aqueous , alcoholic or oily suspension or aqueous or oily solution. Examples of inert carrier substances which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. In this regard, the preparation can be carried out in the form of dry granules or wet granules. Examples of suitable oily carrier substances or solvents are vegetable or animal oils such as sunflower oil or cod liver oil.

For subcutaneous, intraarticular, intraperitoneal or intravenous administration, the active compounds are formulated, if desired, into solutions, suspensions and emulsions with substances suitable for the purpose, such as solubilizers, emulsifiers or other auxiliary substances. Examples of suitable solvents are physiological saline or solutions of alcohols such as ethanol, propanol or glycerol and sugar solutions such as glucose or mannitol, or mixtures of the different solvents mentioned.

Usual auxiliaries such as carrier substances, disintegrants, binders, coatings, bulking agents, glidants or lubricants, flavoring agents, sweeteners and solubilizers can also be used. Auxiliary substances that are often used and may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol and solvents such as sterile water and monohydric or polyhydric alcohols such as glycerol.

The compounds of formula I are preferably prepared in the form of pharmaceutical formulations and administered in the form of dosage units, each unit containing a defined dose of the compound of formula I as active ingredient. For this purpose, the compound of formula I can be administered orally at a dose of 0.01 mg/kg/day to 25.0 mg/kg/day, preferably 0.01 mg/kg/day to 5.0 mg/kg/day, or at 0.001 mg/kg/day It is administered parenterally at a dose of 5 mg/kg/day to 5 mg/kg/day, preferably 0.001 mg/kg/day to 2.5 mg/kg/day. The dose can also be increased in severe cases. However, smaller dosages will also be appropriate in many cases. These data relate to the treatment of adults.

The invention is explained in more detail below with the aid of examples.

Example 1:

Ethyl [4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]acetate

a) Methyl 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylate

Dissolve 8.81g (0.045mol) of pyrimidine-4,6-dicarboxylic acid dimethyl ester in 200ml of DMF, add 6.25g (0.045mol) of 4-fluoro-3-methylbenzylamine, and then stir the mixture at 60°C 48 hours. The solvent was evaporated in vacuo and ethyl acetate was added to the residue. The organic phase was washed with saturated sodium bicarbonate solution and 0.5N HCl, then dried ( _MgSO4 ). After filtration and evaporation of the solvent in vacuo, the residue is stirred in isopropanol. This gave 8.75 g of product, which was reacted further without any further purification.

b) 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylic acid

To 8.75 g (0.02 mol) of 6-(4-fluoro-3-methylbenzylcarbamoyl) pyrimidine-4-carboxylic acid methyl ester (70%), add 150 ml of ethanol, then add 1.89 g (0.022 mol) of NaOH 6ml of aqueous solution. After standing at room temperature for 3 hours, the solvent was evaporated under reduced pressure and water was added to the residue; the pH was then adjusted to <2 with concentrated HCl. The precipitate was filtered off with suction and dried. This gave 5.5 g (94%) of 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylic acid. MS (ES ⁺ ): m/e = 289.09.

c) (4-aminomethylphenyl) ethyl acetate

Dissolve 0.5 g (2.6 nmol) of ethyl (4-cyanophenyl) acetate in 70 ml of ethanol ammonia solution, and then hydrogenate it with Raney nickel at room temperature and normal pressure. After 45 minutes, the mixture was filtered and evaporated. This gave 0.42 g (82%) of ethyl (4-aminomethylphenyl)acetate. MS (ES ⁺ ): m/e = 194.11.

d) [4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]ethyl acetate

Dissolve 1.3g (4.5mmol) of 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylic acid and 1.042g (5.4mmol) of (4-aminomethylphenyl)ethyl acetate in 30 ml of DMF, then 1.02 g (4.9 mmol) of dicyclohexylcarbodiimide and 0.607 g (4.5 mmol) of hydroxybenzotriazole were added at 5°C. The mixture was stirred for 5 hours and filtered off with suction. The solvent was removed in vacuo and ethyl acetate was added to the residue; the solution was washed with saturated aqueous NaHCO ₃ . The organic phase was dried ( _MgSO4 ), filtered and evaporated under reduced pressure. This gave 2.66 g of product, which was further purified by preparative HPLC. MS (ES ⁺ ): m/e = 464.19.

Example 2:

[4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]acetic acid

To 2.4g (5.2mmol) [4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]ethyl acetate, add 150ml water, then 10 ml of water and 0.227 g (5.7 mmol) of NaOH were added. After stirring at room temperature for 5 days, the solvent was evaporated under reduced pressure and the residue was stirred in ethanol, which was then filtered off. This gave 1.51 g (67%) of [4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]acetic acid. MS (ES ⁺ ): m/e = 436.15.

Example 3

Pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methoxybenzylamide)

a) Synthesis of 6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carboxylic acid

26 g (88 mmol) of 6-(3-methoxybenzylcarbamoyl) pyrimidine-4-carboxylic acid methyl ester (by reacting pyrimidine-4,6-dicarboxylic acid dimethyl ester with 3-methoxybenzylamine ) was dissolved in 100 ml of tetrahydrofuran, then 104 ml (1.2 equivalents) of 1 molar lithium hydroxide aqueous solution was added, and the reaction mixture was stirred at room temperature for 18 hours.

Most of the solvent used was then distilled off under reduced pressure and the insoluble by-product was filtered off from the residue; the filtrate was then acidified with 20% aqueous citric acid. 6-(3-Methoxybenzylcarbamoyl)pyrimidine-4-carboxylic acid crystallized out in the form of pale yellow crystals, which were filtered off.

This gave 19 g (66.2 mmol) of 6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carboxylic acid (yield: 75% of theory; MS (ES ⁺ ): m/e=287.8).

b) Methyl 4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)benzoate

4.3g of 6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carboxylic acid (15mmol) obtained from a) was dissolved in 50ml of anhydrous N,N-dimethylformamide, and then heated at 0°C and Add 3.3g (16.5mmol) 4-(aminomethyl) methyl benzoate hydrochloride, 5.4g (16.5mmol) O-[(cyanoethoxycarbonylmethylene)amino]-N continuously under stirring, N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 4.6 ml triethylamine (33 mmol). The reaction mixture was stirred at 0 °C for 1 hour, then at room temperature for 12 hours.

For work-up, the solvent is distilled off under reduced pressure and 100 ml of dichloromethane are added to the residue. The organic phase was washed with 100 ml of saturated aqueous sodium bicarbonate and then with 3 x 100 ml of water. After drying the organic phase with Na ₂ SO ₄ , the solvent was distilled off under reduced pressure. The oily residue was triturated with a little diethyl ether, during which time colorless crystals crystallized. After the reaction product was filtered out and washed with n-pentane, 6.6 g of methyl 4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)benzoate (light yellow crystals). According to LC-MS analysis, the purity of the reaction product was 88% (MS(ES ⁺ ): m/e=435.2).

c) 4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)benzoic acid

6.6 g of the methyl ester obtained in b) were dissolved in 100 ml of tetrahydrofuran, then 36 ml (2.4 equivalents) of 1 molar lithium hydroxide solution were added, and the reaction mixture was stirred for 4 hours while refluxing the solvent.

The solvent was then distilled off under reduced pressure. After adding 50 ml of water, the mixture was filtered through Celite(R) filter aid and the filtrate was acidified with 2N hydrochloric acid solution. The reaction product precipitated out upon acidification and was then filtered off.

Thus obtained 4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)benzoic acid [yield is 48% of theoretical value] of 3.05g light yellow crystal %; MS (ES ⁺ ): m/e = 421.31]. d) pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methoxybenzylamide)

420 mg of 4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)benzoic acid obtained from c) was dissolved in 5 ml of dry N,N-dimethyl methyl formamide, then add 115μl diethylamine and 361mg O-[(cyanoethoxycarbonylmethylene)amino]-N,N,N',N'-tetramethylurea successively under stirring at 0°C Tetrafluoroborate (TOTU) and 153 μl triethylamine, and the reaction mixture was stirred at 0° C. for 1 hour, then at room temperature for 12 hours.

For work-up, the solvent is distilled off under reduced pressure and 100 ml of dichloromethane are added to the residue. The organic phase was washed with 30 ml of a saturated aqueous solution of sodium bicarbonate and then with 3 x 30 ml of water. After drying the organic phase with Na ₂ SO ₄ , the solvent was distilled off under reduced pressure. The oily residue was purified by column chromatography on silica gel (40-63μ) using ethyl acetate/n-heptane (mixing ratio 2:1) as mobile phase. After evaporation of the solvent, an oily residue is obtained which slowly crystallizes after addition of a small amount of diethyl ether.

This gave 270 mg of pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methoxybenzylamide) as colorless crystals (yield is theoretical 57% of [MS (ES ⁺ ): m/e = 476.40]).

Example 62

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(pyridin-4-ylmethyl)amide]

a) Synthesis of 6-[(pyridin-4-ylmethyl)carbamoyl]pyrimidine-4-carboxylic acid

9.7 g (35.7 mmol) of 6-[(pyridin-4-ylmethyl)carbamoyl]pyrimidine-4-carboxylic acid methyl ester (by adding pyrimidine-4,6-dicarboxylic acid dimethyl ester with pyridin-4-yl methylamine) was dissolved in 80 ml tetrahydrofuran and 40 ml water, then 40 ml 1M aqueous NaOH was added and the reaction mixture was then stirred at room temperature for 2 hours.

For work-up, the reaction mixture was concentrated under reduced pressure on a rotary evaporator to half the initial volume. The residue was then acidified with 22 ml of 2N aqueous hydrochloric acid, and the reaction mixture was concentrated to dryness on a rotary evaporator.

This gave 12.2 g of product as a colorless solid, which was reacted further directly as described in 62b).

b) Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[(pyridin-4-ylmethyl)amide]

12.2 g of the compound obtained from 62a) was dissolved in 150 ml of anhydrous DMF, and then 6.63 g (35.7 mmol) of 5-aminomethyl-2,3-dihydrobenzofuran hydrochloride, 11.7 g (35.7 mmol) of )O-[(cyanoethoxycarbonylmethylene)amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 20ml triethylamine, while the mixture Stir at 0°C; after the addition is complete, the reaction mixture is stirred at 0°C for 1 hour, then at room temperature for 4 hours.

For work-up, the solvent is distilled off under reduced pressure and 200 ml of dichloromethane are added to the residue. The organic phase is then washed twice with a saturated aqueous solution of sodium bicarbonate and once with water and then dried over sodium sulfate; the solvent is then removed under reduced pressure on a rotary evaporator. After the addition of a small amount of diethyl ether, the reaction product resulting as an oily residue precipitates out in the form of pink crystals. For further purification, the reaction product was recrystallized twice from 200 ml of isopropanol.

This gives 10 g (25.6 mmol) of pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[(pyridin-4-ylmethyl) Amide] (yield is 72% of theoretical value, based on two-step reaction;

MS (ES ⁺ ): 390.08).

¹ H-NMR (400MHz, d6-DMSO): [δ]=3.13(t, J=8.6Hz, 2H), 4.42(d, J=6.4Hz, 2H), 4.48(t, J=8.6Hz, 2H ), 4.54(d, J=6.4Hz, 2H), 6.69(d, J=8Hz, 1H), 7.07(m, 1H), 7.22(m, 1H), 7.31(m, 2H), 8.46(m, 1H), 8.50(m 2H), 9.47(m, 1H), 9.58(t, J=6.4Hz, 1H), 9.80(t, J=6.4Hz, 1H).

Example 117

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(morpholine-4-carbonyl)benzylamide]

a) Synthesis of 6-[(2,3-dihydrobenzofuran-5-ylmethyl)carbamoyl]pyrimidine-4-carboxylic acid

16.1 g (51 mmol) of 6-[(2,3-dihydrobenzofuran-5-ylmethyl)carbamoyl]pyrimidine-4-carboxylic acid methyl ester (by adding pyrimidine-4,6-dicarboxylic acid dimethyl ester with 5-aminomethyl-2,3-dihydrobenzofuran) was dissolved in 150 ml of tetrahydrofuran, then 62 ml of 1M aqueous LiOH was added, and the reaction mixture was stirred at room temperature for 2 hours.

For work-up, the reaction mixture was concentrated under reduced pressure on a rotary evaporator. 100 ml of water were then added to the crude product, and after addition of activated carbon, the solution was filtered through a clear layer of Celite (R). The resulting mother liquor was then acidified by adding 2N aqueous HCl, and the reaction product slowly precipitated out in the form of colorless crystals.

After filtering off the reaction product and drying, 8.3 g (27 mmol) of the product were obtained as a colorless solid, which was then directly reacted further to give 117b; yield 53% of theory. MS (ES ⁺ ): 300.1.

b) Synthesis of methyl 4-[({6-[(2,3-dihydrobenzofuran-5-ylmethyl)carbamoyl]pyrimidine-4-carbonyl}amino)methyl]benzoate

4.7g (15.7mmol) of the compound obtained by a) was dissolved in 30ml of anhydrous DMF, and then successively added 3.5g (17.3mmol) of methyl 4-aminomethylbenzoate, 5.7g (17.3mmol) of O-[( cyanoethoxycarbonylmethylene)amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 4.8ml triethylamine, while the mixture was heated at 0°C Stir. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 hour, then at room temperature for 8 hours.

For work-up, the solvent is distilled off under reduced pressure and 100 ml of dichloromethane are added to the residue. The organic phase is then washed twice with a saturated aqueous solution of sodium bicarbonate and once with water and then dried over sodium sulfate; the solvent is then removed under reduced pressure on a rotary evaporator. After the addition of a small amount of diethyl ether, the reaction product resulting as an oily residue precipitates out in the form of pale yellow crystals.

This gave 6.8 g (15.2 mmol) of 4-[({6-[(2,3-dihydrobenzofuran-5-ylmethyl)carbamoyl]pyrimidine-4-carbonyl}amino)methyl]benzene Methyl formate, the yield is 97% of theory. MS (ES ⁺ ): 447.1.

c) 4-[({6-[(2,3-dihydrobenzofuran-5-ylmethyl)carbamoyl]pyrimidine-4-carbonyl}amino)methyl]benzoic acid

6.28g (14mmol) 4-[({6-[(2,3-dihydrobenzofuran-5-ylmethyl)carbamoyl]pyrimidine-4-carbonyl}amino)methyl]benzoate (see 117b) A suspension was formed in 150 ml tetrahydrofuran and 70 ml water, then 16.9 ml 1N aqueous NaOH was added and the reaction mixture was stirred at room temperature for 24 hours.

For work-up, the reaction mixture was concentrated under reduced pressure on a rotary evaporator to about 50 ml, then 100 ml of ice water were added. The mixture was then acidified with 2N aqueous HCl and the reaction product precipitated out as pale yellow crystals.

The reaction product was filtered off, washed with a small amount of water and dried to give 5.4 g (12.5 mmol) of the product as a colorless solid, which was directly reacted further to give 117d; yield: 89% of theory.

MS (ES ⁺ ): 433.2.

¹ H-NMR (400MHz, d6-DMSO): [δ]=3.13(t, J=8.7Hz, 2H), 4.43(d, J=6.1Hz, 2H), 4.48(t, J=8.7Hz, 2H ), 4.59(d, J=6.3Hz, 2H), 6.69(d, J=8.1Hz, 1H), 7.07(m, 1H), 7.22(m, 1H), 7.44(m, 2H), 7.88(m , 1H), 7.90(m, 1H), 8.47(d, J=1.5Hz, 1H), 9.46(d, J=1.3Hz, 1H), 9.56(t, J=6.3Hz, 1H), 9.76(t , J=6.3Hz, 1H), 12.90 (br s, 1H).

d) pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(morpholine-4-carbonyl)benzylamide]

Dissolve 432 mg (1 mmol) of the compound obtained from c) in 5 ml of anhydrous DMF, then add 96 μl (1.1 mmol) of morpholine, 361 mg (1.1 mmol) of O-[(cyanoethoxycarbonylmethylene) amino ]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 155 µl of triethylamine while stirring the mixture at 0°C. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 hour, then at room temperature for 8 hours.

For work-up, the solvent is distilled off under reduced pressure and 30 ml of dichloromethane are added to the residue. The organic phase was then washed twice with saturated aqueous sodium bicarbonate, once with water and dried over sodium sulfate; the solvent was then removed under reduced pressure on a rotary evaporator. The crude product obtained as an oily residue was purified by chromatography on silica gel (40-63 μ; mobile phase: ethyl acetate/methanol=20/1). After removing the mobile phase by distillation under reduced pressure, an oily reaction product was obtained, which precipitated as colorless crystals after adding diethyl ether. 340 mg (068 mmol) of colorless crystals are obtained, yield: 68% of theory.

MS(ES ⁺ ): 502.27.

¹ H-NMR (500MHz, d6-DMSO): [δ]=2.60(m, 2H), 3.4-3.6(br m, 8H), 4.42(d, J=6.5Hz, 2H), 4.48(t, J =8.6Hz, 2H), 4.56(d, J=6.5Hz, 2H), 6.68(d, J=8.3Hz 1H), 7.07(d, J=6.5Hz, 1H), 7.22(s, 1H), 7.88 (m, 4H), 8.46(m, 1H), 9.46(m, 1H), 9.57(t, J=6.5Hz, 1H), 9.75(t, J=6.5Hz, 1H).

The following compounds were prepared in a similar manner.

Table 1:

Pharmacological Example

Determination of the enzymatic activity of the catalytic domain of human collagenase 3 (MMP-13)

The protein was obtained from INVITEK, Berlin (cat. no. 30100803) in the form of an inactive zymogen. Activated zymogen:

2 volume parts of zymogen were incubated with 1 volume part of APMA solution at 37°C for 1.5 hours. APMA solution was prepared from a solution of 10 mmol/L p-aminophenylmercuric acetate in 0.1 mmol/L NaOH by dilution with 3 parts by volume of tris/HCl buffer, pH 7.5 (see below). Adjust the pH to 7.0 to 7.5 by adding 1 mmol/L HCl. After the enzyme was activated, it was diluted with tris/HCl buffer to a concentration of 1.67 μg/ml.

To measure enzyme activity, 10 μl of enzyme solution was incubated with 10 μl of 3% (v/v) dimethylsulfoxide buffer solution for 15 minutes (reaction 1). To measure the activity of enzyme inhibitors, 10 μl of enzyme solution was incubated with 10 μl of 3% (v/v) DMSO buffer solution containing enzyme inhibitors (reaction 2).

In the case of Reaction 1 and Reaction 2, after adding 10 μl of 3% (v/v) DMSO aqueous solution containing 0.75 mmol substrate/L, by fluorescence spectrum (328nm (extinction)/393nm (emission)) Monitor the enzymatic reaction.

Enzyme activity is expressed in increments of extinction/min.

The inhibitor effect was calculated as percent inhibition using the following formula:

% Inhibition = 100 - [(increase in extinction/min in Reaction 2)/(increase in extinction/min in Reaction 1)*100].

IC50, the inhibitory concentration required to inhibit the enzyme activity by 50%, was determined by plotting the percent inhibition at different inhibitor concentrations.

The buffer solution contained 0.05% Brij (Sigma, Deisenhofen, Germany) and 0.1 mol Tris/HCl/L, 0.1 mol NaCl/L and 0.01 mol CaCl _{2 /} L (pH=7.5). The enzyme solution contained 1.67 μg enzyme domain/mL.

The substrate solution contains 0.75mmol/L fluorescent substrate (7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-3-(2′,4′-dinitrophenyl )-L-2,3-Diaminopropionyl-Ala-Arg-NH ₂ (Bachem, Heidelberg, Germany).

Table 2 below lists the results.

Table 2: Example IC ₅₀ MMP13 (nM) Example IC ₅₀ MMP13 (nM) Example IC ₅₀ MMP13 (nM) Example IC ₅₀ MMP13 (nM) 3 4 73 25 96 50 126 2.3 4 13 74 30 98 20 127 3.3 6 20 75 70 99 50 128 60 36 10 75a 34 101 2 129 twenty two 39 30 76 twenty three 105 twenty three 135 20 44 200 78 3 106 40 136 20 62 20 82 30 109 50 137 40 63 9 83 5 112 45 138 50 64 10 84 3.2 114 50 139 10 65 15 85 3.5 115 20 144 9 66 10 86 2.5 117 8 147 3 67 15 87 twenty four 118 2.4 150 80 68 twenty two 88 33 119 35 151 9 69 32 89 18 121 30 153 15 70 twenty four 93 20 122 43 154 twenty two 71 9 94 20 125 4 158 4 72 10

The enzymatic activity of the catalytic domains of human neutral collagenase (MMP-8) and human stromelysin (MMP-3) was determined.

Human neutral collagenase and human stromelysin were prepared in the form of active catalytic domains as described by Weithmann et al., Inflamm Res, 46 (1997), pp. 246-252. The determination of the enzyme activity and the determination of the inhibitory effect of the inhibitors on the enzyme activity were also carried out according to the method described in this publication.

The compounds described in the examples above have in all cases _IC50 values greater than 100 000 nM when assayed for human neutral collagenase and human stromelysin. Thus, these compounds did not in fact inhibit MMP 3 and 8 activity.

Claims (8)

1. The compound of formula I

and/or all stereoisomeric forms of compounds of formula I and/or mixtures of these forms in any proportion and/or physiologically tolerable salts of compounds of formula I, wherein For case a) R1 is a hydrogen atom or -(C ₁ -C ₆ )-alkyl, R2 is -(C ₁ -C ₆ )-alkyl, wherein the alkyl is substituted once, twice or three times by the following substituents 1.-(C ₁ -C ₆ )-alkyl-O-(C ₆ -C ₁₄ )-aryl, 2.-(C ₀ -C ₆ )-Alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkyl, wherein R8 is i) a hydrogen atom or ii) -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of each other once, twice or three times by the following substituents: -NH ₂ , -CN, -OH, -C( O)-OH, -C(O)-O-(C ₁ -C ₆ )-alkyl, -C(O)-NH-OH, NO ₂ or halogen, or iii) OH, 3.-(C(O)-N(R9)-(R10), wherein R9 and R10 are identical or different and independently of each other: i) a hydrogen atom or ii) -(C ₁ -C ₆ )-alkyl, or R9 and R10 form a 5-, 6- or 7-membered saturated ring together with the nitrogen atom to which they are attached, wherein heteroatoms selected from oxygen, sulfur and nitrogen can also replace one or two additional carbon atoms, in nitrogen In the case of , the nitrogen atoms can independently of each other be unsubstituted or substituted by (C ₁ -C ₆ )-alkyl, 4. -(C ₆ -C ₁₄ )-aryl, wherein aryl is substituted independently of one another once, twice or three times by the following substituents: 4.1)-(C ₀ -C ₆ )-Alkyl-C(O)-O-R8, wherein R8 has the meanings stated above, 4.2)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings stated above, 4.3)-(C ₀ -C ₆ )-Alkyl-C(O)-NH-CN, 4.4) -(C ₀ -C ₆ )-Alkyl-C(O)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is saturated or unsaturated monocyclic or bicyclic, 3- to 10 -membered heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms selected from nitrogen, oxygen and sulfur, and is unsubstituted or substituted once or twice independently of each other by the following substituents or three times: a) halogen, b) cyano, c) nitro, d) hydroxyl, e) amino groups, f)-C(O)-O-(C ₁ -C ₆ )-alkyl, g)-C(O)-OH, h) -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, i) -O-(C ₁ -C ₆ )-alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen or -N(R9)-(R10), j)=O, k)-Het, l) -(C ₂ -C ₆ )-alkenyl, wherein alkenyl is unsubstituted or substituted once, twice or three times by halogen or -N(R9)-(R10), or m)-(C ₂ -C ₆ )-alkynyl, wherein alkynyl is unsubstituted or substituted once, twice or three times by halogen or -N(R9)-(R10), 4.5)-(C ₀ -C ₆ )-Alkyl-C(O)-(C ₀ -C ₆ )-Alkyl-OH, 4.6)-O-(C ₀ -C ₆ )-alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings stated above, 4.7)-S(O) _y- (C ₁ -C ₆ )-alkyl-C(O)-O-R8, wherein R8 has the meanings stated above and y is 1 or 2, 4.8)-S(O) _z- (C ₁ -C ₆ )-Alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings stated above and z is 0,1 or 2, 4.9)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-N(R9)-(R10), where R8, R9 and R10 has the meaning stated above, 4.10)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-Het, wherein R8 has the above-mentioned meanings, Het has the above-mentioned and are unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above, 4.11)-(C ₀ -C ₆ )-alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above, 4.12)-(C ₀ -C ₆ )-Alkyl-N(R9)-(R10), wherein R9 and R10 have the meanings stated above, 4.13) -(CH ₂ ) _y -N(R8)-C(O)-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or independently of each other by the groups mentioned above a) to m) substituted once, twice or three times and y is 1 or 2, 4.14)-(C ₀ -C ₄ )-alkyl-N(R8)-C(O)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above, 4.15)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or independently of each other mentioned above The groups a) to m) are substituted once, twice or three times, 4.16)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or independently of each other by the above The groups a) to m) mentioned are substituted once, twice or thrice, 4.17)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkenyl, wherein alkenyl is unsubstituted or independently of each other Substituted once, twice or three times by the groups a) to m) mentioned above, 4.18)-(C ₀ -C ₄ )-alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-alkynyl, wherein the alkynyl is unsubstituted or independently of each other replaced by the above The groups a) to m) mentioned are substituted once, twice or thrice, 4.19)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl radicals are unsubstituted or substituted independently of each other once, twice or three times by the abovementioned groups a) to m), 4.20)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or independently of each other The groups a) to m) mentioned above are substituted once, twice or three times, 4.21)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-(C ₀ -C ₆ )-Alkyl-N(R11)-R12, wherein R8 has the meanings described above , R11 and R12 are the same or different and independently of each other are: 4.21.1) Hydrogen atoms, 4.21.2)-(C ₁ -C ₆ )-Alkyl, 4.21.3)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or independently of one another by the groups a) to m) mentioned above instead of once, twice or thrice, 4.21.4)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or substituted independently of each other once, twice or three times by the abovementioned groups a) to m), 4.21.5) -C(O)-(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or independently of one another by the groups a) to m) mentioned above three times, 4.21.6)-C(O)-(C ₃ -C ₆ )-cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted independently of one another once, twice once or three times, 4.21.7)-C(O)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or independently of each other by the groups mentioned above a) to m) are substituted once, twice or three times, 4.21.8)-C(O)-(C ₀ -C ₆ )-Alkyl-Het, where Het is unsubstituted or substituted once, twice independently of each other by the groups a) to m) mentioned above or three times, 4.21.9) -SO ₂ -(C ₀ -C ₆ )-alkyl, wherein the alkyl groups are unsubstituted or substituted independently of one another once, twice or three times by the groups a) to m) mentioned above, 4.21.10) -NH-SO ₂ -(C ₀ -C ₆ )-alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or independently of one another by the groups a) to m) mentioned above three times, 4.21.11)-SO ₂ -(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl-(C ₀ -C ₆ )-alkyl, where the aryl groups are unsubstituted or mutually independently substituted one, two or three times by the groups a) to m) mentioned above, 4.21.12) -SO ₂ -(C ₀ -C ₆ )-alkyl-Het, where Het is unsubstituted or substituted one, two or three times independently of each other by the groups a) to m) mentioned above , 4.22)-(C ₀ -C ₄ )-Alkyl-N(R8)-S(O) ₂ -(C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl are unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above, and R8 has the meanings stated above, 4.23)-(C ₀ -C ₄ )-Alkyl-N(R8)-S(O) ₂ -(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or independently of each other replaced by the above The groups a) to m) mentioned are substituted once, twice or three times, and R8 has the meanings stated above, 4.24)-(C ₀ -C ₄ )-Alkyl-N(R8)-S(O) ₂ -N(R8)-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or mutually independently substituted one, two or three times by the groups a) to m) mentioned above, and R8 has the meanings stated above, 4.25)-(C ₀ -C ₄ )-Alkyl-N(R8)-S(O) ₂ -N(R8)-(C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-aryl wherein the aryl groups are unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above, and R8 has the meanings stated above, 4.26)-(C ₀ -C ₄ )-Alkyl-N(R8)-S(O) ₂ -N(R8)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or are substituted one, two or three times independently of each other by the groups a) to m) mentioned above, and R8 has the meanings stated above, 4.27)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-N(R8)-SO ₂ -R13, wherein R8 has the meanings stated above and R13 is -(C ₁ - C ₆ )-alkyl or -(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, 4.28)-(C ₀ -C ₄ )-Alkyl-S(O) ₂ -N(R8)-(C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl are unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above, and R8 has the meanings stated above, 4.29)-(C ₀ -C ₄ )-Alkyl-S(O) ₂ -N(R8)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or independently of each other replaced by the above The groups a) to m) mentioned are substituted once, twice or three times, and R8 has the meanings stated above, 4.30)-(C ₀ -C ₄ )-Alkyl-S(O) ₂ -N(R8)-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or are independently mentioned above The groups a) to m) are substituted once, twice or three times, and R8 has the meanings stated above, 4.31)-(C ₀ -C ₄ )-Alkyl-S(O) _2- (C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or independently of each other one, two or three times by the groups a) to m) mentioned above, 4.32)-(C ₀ -C ₄ )-Alkyl-S(O) ₂ -(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or independently of each other by the groups mentioned above a) to m) are substituted once, twice or three times, 4.33)-O-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or substituted independently of each other once, twice or three times by the abovementioned groups a) to m), 4.34)-(C ₀ -C ₄ )-Alkyl-Het, wherein Het is unsubstituted or substituted independently of each other once, twice or three times by the abovementioned groups a) to m), or 4.35)-Phenyl, wherein phenyl is unsubstituted or substituted once, twice or three times by the following substituents: 4.35.1) halogen, 4.35.2)-(C ₁ -C ₆ )-alkyl, 4.35.3)-O-(C ₁ -C ₆ )-alkyl, or 4.35.4) -S(O) ₂ -R16, wherein R16 is (C ₁ -C ₆ )-alkyl or -NH ₂ , 5.-C(O)-N(R8)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or independently of each other mentioned above 4.1) to 4.35) or 4.4) a) to 4.4) m) are substituted once, twice or three times, and R8 has the meanings stated above, 6.-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het has the above-mentioned meanings and is unsubstituted or independently of each other by the above-mentioned groups 4.1) to 4.35) or 4.4) a) to 4.4) m) are substituted once, twice or three times, and R8 has the meaning stated above, or 7. -NH-(C ₆ -C ₁₄ )-aryl, wherein aryl is unsubstituted or substituted independently of one another by the abovementioned groups 4.1) to 4.35) or 4.4) a) to 4.4) m) once, twice or three times, or 8.-NH-Het, wherein Het has the meanings stated above and is unsubstituted or substituted independently of one another once, twice once or three times, R3, R4, R5, R6 and R7 are identical or different and independently of each other are: 1. Hydrogen atom, 2. Halogen, 3. -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, 4. -O-(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, or 5. -S-(C ₁ -C ₆ )-alkyl, or R4 and R5 or R5 and R6 together with the carbon atoms to which they are attached in each case independently form a 5- or 6-membered ring which is aromatic or saturated and contains 0, 1 or 2 Heteroatoms selected from oxygen, nitrogen or sulfur, wherein said ring is unsubstituted or substituted once or twice by halogen on one or several carbon atoms, other groups R3, R6 and R7 or R3, R4 and R7 have the meanings of 1. to 5. mentioned above, or, for case b) R1 is a hydrogen atom or -(C ₁ -C ₆ )-alkyl, R2 is -(C ₁ -C ₆ )-alkyl, wherein the alkyl is substituted once, twice or three times by the following substituents: 1.-C(O)-O-R8', wherein R8' is 1.1) hydrogen atom or 1.2)-(C ₁ -C ₆ )-Alkyl, 2. -(C ₁ -C ₆ )-Alkyl-O-R8', wherein R8' has the meanings stated above, 3. -(C ₆ -C ₁₄ )-aryl, wherein aryl is substituted independently of one another once, twice or three times by the following substituents: 4. 3.1) -(C ₂ -C ₆ )-alkyl-C(O)-O-R8', wherein R8' has the meanings mentioned above, 3.2) -O-(C ₁ -C ₆ )-alkyl-C(O)-O-R8', wherein R8' has the meanings stated above, 3.3)-N(R14)-(R15), wherein R14 and R15 form a 5-, 6- or 7-membered saturated ring together with the nitrogen atom to which they are attached, wherein the heteroatom selected from oxygen, sulfur and nitrogen is also One or two further carbon atoms may be substituted, in the case of nitrogen, the nitrogen atoms may independently of one another be unsubstituted or substituted by (C ₁ -C ₆ )-alkyl, 3.4) -(CH ₂ ) _k -N(R9')-(R10'), wherein k is 2, 3, 4 or 5, R9' and R10' are identical or different and independently of each other are: 3.4.1) Hydrogen or 3.4.2) -(C ₁ -C ₆ )-alkyl, or R9' and R10' together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, wherein a heteroatom selected from oxygen, sulfur and nitrogen can also replace one or two additional carbon atoms, In the case of nitrogen, the nitrogen atoms can independently of one another be unsubstituted or substituted by (C ₁ -C ₆ )-alkyl, 3.5) -O-(C ₂ -C ₆ )-alkyl-N(R9')-R10', wherein R9' and R10' have the meanings stated above, 3.6) -N(R8')-C(O)-(C ₁ -C ₆ )-alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by the following substituents: 3.6.1) Halogen, 3.6.2) cyano group, 3.6.3) Nitro, 3.6.4) Hydroxyl, 3.6.5) amino group, 3.6.6)-C(O)-O-(C ₁ -C ₆ )-alkyl, or 3.6.7) -C(O)-OH, and R8' has the meanings stated above, 3.7) -Phenyl, wherein phenyl is unsubstituted or substituted once, twice or three times by the following substituents: 3.7.1) Halogen, 3.7.2) -(C ₁ -C ₆ )-Alkyl, 3.7.3)-O-(C ₁ -C ₆ )-alkyl, 3.7.4) -S(O) ₂ -R16', wherein R16' is (C ₁ -C ₆ )-alkyl or -NH ₂ , 4. Het, wherein Het is a saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring system containing 1, 2 or 3 identical or different compounds selected from nitrogen, oxygen and sulfur Heteroatom, and is unsubstituted or substituted once, twice or thrice by the following substituents: 4.1) Halogen, 4.2) cyano, 4.3) Nitro, 4.4) Hydroxyl, 4.5) amino group, 4.6)-C(O)-O(C ₁ -C ₆ )-alkyl, 4.7) -C(O)-OH, 4.8) -(C ₁ -C ₆ )-Alkyl, wherein the alkyl group is unsubstituted or substituted once, twice or three times by halogen, 4.9) -O-(C ₁ -C ₆ )-Alkyl, wherein the alkyl group is unsubstituted or substituted once, twice or three times by halogen, 4.10) pyridyl, or 4.11) Phenyl, wherein phenyl is unsubstituted or substituted once independently of each other by a group selected from halogen, -(C ₁ -C ₆ )-alkoxy and -(C ₁ -C ₆ )-alkyl or more than once, and R4 and R5 or R5 and R6 together with the carbon atoms to which they are attached in each case independently form a 5- or 6-membered ring which is saturated and contains one or two rings selected from oxygen, nitrogen or heteroatoms of sulfur, wherein said ring is unsubstituted or substituted once or twice by halogen on one or several carbon atoms, the other groups R3, R6 and R7 or R3, R4 and R7 are hydrogen, The proviso is that unsubstituted benzo[1,3]dioxole rings are excluded. 2. The compound of formula I according to claim 1, wherein, for the case of a) R1 is a hydrogen atom or -(C ₁ -C ₆ )-alkyl, R2 is -(C ₁ -C ₆ )-alkyl, wherein the alkyl is substituted once, twice or three times by the following substituents: 1.-(C ₁ -C ₆ )-alkyl-O-(C ₆ -C ₁₄ )-aryl, 2.-(C ₀ -C ₆ )-Alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkyl, wherein R8 is i) a hydrogen atom, ii) -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of each other once, twice or three times by the following substituents: -NH ₂ , -CN, -OH, -C( O)-OH, -C(O)-O-(C ₁ -C ₆ )-alkyl, -C(O)-NH-OH, NO ₂ or halogen, or iii) -OH, 3.-C(O)-N(R9)-(R10), wherein R9 and R10 are the same or different and independently of each other i) a hydrogen atom or ii) -(C ₁ -C ₆ )-alkyl, or R9 and R10 form a 5-, 6- or 7-membered saturated ring together with the nitrogen atom to which they are attached, wherein heteroatoms selected from oxygen, sulfur and nitrogen can also replace one or two additional carbon atoms, in nitrogen In the case of , the nitrogen atoms can independently of each other be unsubstituted or substituted by (C ₁ -C ₆ )-alkyl, 4. Phenyl, wherein phenyl is substituted one, two or three times independently of each other by the following substituents: 4.1)-(C ₀ -C ₆ )-Alkyl-C(O)-O-R8, wherein R8 has the meanings stated above, 4.2)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings stated above, 4.3)-(C ₀ -C ₆ )-Alkyl-C(O)-NH-CN, 4.4)-(C ₀ -C ₆ )-alkyl-C(O)-(C ₀ -C ₆ )-alkyl-Het, wherein Het is a group selected from the group consisting of azepine, azetidine alkanes, aziridines, benzimidazoles, benzofurans, benzo[1,4]dioxins, 1,3-benzodioxoles, 4H-benzo[1,4]oxanes Ozine, benzoxazole, benzothiazole, benzothiophene, quinazolidin, quinoline, quinoxaline, chroman, cinnoline, 1,2-diazepine, 1,3-di Azepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman , isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, ethylene oxide, piperazine, piperidine, Phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3- Thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1 , 2,3-triazole or 1,2,4-triazole, wherein Het is unsubstituted or independently of each other by The following substituents are substituted once, twice or thrice: a) halogen, b) cyano, c) nitro, d) hydroxyl, e) amino groups, f)-C(O)-O-(C ₁ -C ₆ )-alkyl, g)-C(O)-OH, h) -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, i) -O-(C ₁ -C ₆ )-alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen or -N(R9)-(R10), j)=O, k)-Het, wherein Het is as defined above, l) -(C ₂ -C ₆ )-alkenyl, wherein alkenyl is unsubstituted or substituted once, twice or three times by halogen or -N(R9)-(R10), or m)-(C ₂ -C ₆ )-alkynyl, wherein alkynyl is unsubstituted or substituted once, twice or three times by halogen or -N(R9)-(R10), 4.5)-(C ₀ -C ₆ )-Alkyl-C(O)-(C ₀ -C ₆ )-Alkyl-OH, 4.6)-O-(C ₀ -C ₆ )-alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings stated above, 4.7)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-N(R9)-(R10), wherein R8, R9 and R10 has the meaning stated above, 4.8)-(C ₀ -C ₄ )-Alkyl-N(R8)-S(O) ₂ -(C ₀ -C ₆ )-Alkyl-Het, wherein Het is as defined above and is unsubstituted or are substituted one, two or three times independently of each other by the groups a) to m) mentioned above, and R8 has the meanings stated above, 4.9)-(C ₀ -C ₄ )-Alkyl-S(O) ₂ -(C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-Phenyl, wherein phenyl is unsubstituted or independently of each other one, two or three times by the groups a) to m) mentioned above, 4.10)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-Het, wherein R8 has the above-mentioned meanings, Het has the above-mentioned and are unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above, 4.11)-(C ₀ -C ₆ )-alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-phenyl, wherein phenyl is unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above, 4.12)-(C ₀ -C ₆ )-Alkyl-N(R9)-(R10), wherein R9 and R10 have the meanings stated above, 4.13) -(CH ₂ ) _y -N(R8)-C(O)-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or independently of each other by the groups mentioned above a) to m) substituted once, twice or three times and y is 1 or 2, 4.14)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-(C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-Phenyl, wherein phenyl is unsubstituted or substituted independently of each other once, twice or three times by the groups a) to m) mentioned above, 4.15)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is unsubstituted or independently of each other mentioned above The groups a) to m) are substituted once, twice or three times, 4.16)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkyl, wherein the alkyl groups are unsubstituted or independently of each other by the above The groups a) to m) mentioned are substituted once, twice or thrice, 4.17)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-Alkenyl, wherein alkenyl is unsubstituted or independently of each other Substituted once, twice or three times by the groups a) to m) mentioned above, 4.18)-(C ₀ -C ₄ )-alkyl-N(R8)-C(O)-O-(C ₁ -C ₆ )-alkynyl, wherein the alkynyl is unsubstituted or independently of each other replaced by the above The groups a) to m) mentioned are substituted once, twice or thrice, 4.19)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₀ -C ₆ )-Alkyl-(C ₆ -C ₁₄ )-Phenyl, wherein benzene radicals are unsubstituted or substituted independently of each other once, twice or three times by the abovementioned groups a) to m), 4.20)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-O-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is as defined above and is unsubstituted or independently of each other one, two or three times by the groups a) to m) mentioned above, 4.21)-(C ₀ -C ₄ )-Alkyl-N(R8)-C(O)-(C ₀ -C ₆ )-Alkyl-N(R11)-R12, wherein R8 has the meanings described above , R11 and R12 are the same or different and independently of each other are: 4.21.1) Hydrogen atoms, 4.21.2)-(C ₁ -C ₆ )-Alkyl, 4.21.3)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-phenyl, wherein phenyl is unsubstituted or independently of one another by the groups a) to m) mentioned above instead of once, twice or thrice, 4.21.4)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is as defined above and is unsubstituted or substituted once, twice independently of each other by the groups a) to m) mentioned above or three times, 4.21.5) -C(O)-(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or independently of one another by the groups a) to m) mentioned above three times, 4.21.6)-C(O)-(C ₃ -C ₆ )-cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted independently of one another once, twice once or three times, 4.21.7)-C(O)-(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-phenyl, wherein phenyl is unsubstituted or independently of each other by the above-mentioned groups a) to m) are substituted once, twice or three times, 4.21.8)-C(O)-(C ₀ -C ₆ )-alkyl-Het, wherein Het is as defined above and is unsubstituted or independently of each other by the above-mentioned groups a) to m) instead of once, twice or thrice, 4.21.9) -SO ₂ -(C ₀ -C ₆ )-alkyl, wherein the alkyl groups are unsubstituted or substituted independently of one another once, twice or three times by the groups a) to m) mentioned above, 4.21.10) -NH-SO ₂ -(C ₀ -C ₆ )-alkyl, wherein alkyl is unsubstituted or substituted independently of one another once, twice or independently of one another by the groups a) to m) mentioned above three times, 4.21.11)-SO ₂ -(C ₀ -C ₆ )-alkyl-(C ₆ -C ₁₄ )-phenyl-(C ₀ -C ₆ )-alkyl, where the phenyl groups are unsubstituted or each other independently substituted one, two or three times by the groups a) to m) mentioned above, 4.21.12) -SO ₂ -(C ₀ -C ₆ )-alkyl-Het, wherein Het is as defined above and is unsubstituted or substituted once independently of each other by the groups a) to m) mentioned above , two or three times, 4.22)-O-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is as defined above and is unsubstituted or substituted once, twice independently of each other by the groups a) to m) mentioned above or three times, or 4.23)-(C ₀ -C ₄ )-Alkyl-Het, wherein Het is as defined above and is unsubstituted or substituted one, two or three times independently of each other by the groups a) to m) mentioned above , 5.-C(O)-N(R8)-(C ₀ -C ₆ )-alkyl-phenyl, wherein phenyl is unsubstituted or independently of each other by the above-mentioned groups 4.1) to 4.23) or 4.4) a) to 4.4) m) are substituted once, twice or three times, and R8 has the meanings stated above, or 6. -C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-Het, wherein Het is azepine, azetidine, aziridine, benzimidazole, benzo Furan, benzo[1,4]dioxin, 1,3-benzodioxole, 4H-benzo[1,4]oxazine, benzoxazole, benzothiazole, benzo Thiophene, quinazolidin, quinoline, quinoxaline, chroman, cinnoline, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxol, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazole, phenoline, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyran oxazine, pyridine, pyrimidine, pyridimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, sulfur Morpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4 - triazole, and Het is unsubstituted or substituted independently of each other by the above-mentioned groups 4.1) to 4.4) or 4.4) a) to 4.4) m) once, twice or three times, and R8 has the above-mentioned the meaning of R3, R4, R5, R6 and R7 are identical or different and independently of each other are: 1. Hydrogen atom, 2. Halogen, 3. -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, or 4. -O-(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, or R4 and R5 or R5 and R6 together with the carbon atoms to which they are attached in each case independently form a dioxane, dioxole, dihydrofuran or furan ring, wherein said ring is unsubstituted or substituted once or twice by halogen on one or several carbon atoms, the other groups R3, R6 and R7 or R3, R4 and R7 have the meanings of 1. to 4. mentioned above, or for case b), R1 is a hydrogen atom or -(C ₁ -C ₄ )-alkyl, R2 is -(C ₁ -C ₄ )-alkyl, wherein the alkyl is substituted once, twice or three times by the following substituents: 1.-C(O)-O-R8', wherein R8' is: 1.1) hydrogen atom or 1.2)-(C ₁ -C ₄ )-Alkyl, 2. -(C ₁ -C ₄ )-Alkyl-O-R8', wherein R8' has the meanings stated above, 3. Phenyl, wherein the phenyl groups are independently substituted one, two or three times by the following substituents: 3.1) -(C ₂ -C ₄ )-alkyl-C(O)-O-R8', wherein R8' has the meanings stated above, 3.2) -O-(C ₁ -C ₄ )-alkyl-C(O)-O-R8', wherein R8' has the meanings stated above, 3.3) -N(R14)-(R15), wherein R14 and R15 together with the nitrogen atom to which they are attached form a group derivable from: pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazole Alkane, piperazine, isoxazolidine, morpholine, isothiazolidine or thiomorpholine, in the case of nitrogen, the nitrogen atoms can independently of one another be unsubstituted or be replaced by (C ₁ -C ₄ )-alkyl replaced by 3.4) -(CH ₂ ) _k -N(R9')-R(10'), wherein k is 2, 3, 4 or 5, R9' and R10' are identical or different and independently of each other: 3.4.1) A hydrogen atom or 3.4.2) -(C ₁ -C ₆ )-alkyl, or R9' and R10' together with the nitrogen atom to which they are attached form a group derived from: pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, methazolidine phenoline, isothiazolidine or thiomorpholine, in the case of nitrogen, the nitrogen atoms may independently of one another be unsubstituted or substituted by (C ₁ -C ₄ )-alkyl, 3.5) -O-(C ₂ -C ₆ )-alkyl-N(R9')-R10', wherein R9' and R10' have the meanings stated above, 3.6) -N(R8')-C(O)-(C ₁ -C ₆ )-alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by the following substituents: 3.6.1) Halogen, 3.6.2) cyano group, 3.6.3) Nitro, 3.6.4) Hydroxyl, 3.6.5) amino group, 3.6.7)-C(O)-O-(C ₁ -C ₆ )-alkyl, or 3.6.8) -C(O)-OH, and R8' has the meanings stated above, 3.7) -Phenyl, wherein phenyl is unsubstituted or substituted once, twice or three times by the following substituents: 3.7.1) Halogen, 3.7.2) -(C ₁ -C ₆ )-Alkyl, 3.7.3) -O-(C ₁ -C ₆ )-alkyl, or 3.7.4) -S(O) ₂ -R16', wherein R16' is (C ₁ -C ₆ )-alkyl or -NH ₂ , 4. Het, wherein Het is azepine, azetidine, aziridine, benzimidazole, benzofuran, benzo[1,4]dioxin, 1,3-benzodiox Heterocyclopentene, 4H-benzo[1,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazolidine, quinoline, quinoxaline, chroman, cinnoline , 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole , indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine , oxazole, ethylene oxide, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine , tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3, 5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4-triazole, and Het is unsubstituted or substituted once, twice independently of each other by the following substituents times or times: 4.1) Halogen, 4.2) cyano, 4.3) Nitro, 4.4) Hydroxyl, 4.5) amino group, 4.6)-C(O)-O(C ₁ -C ₆ )-alkyl, 4.7) -C(O)-OH, 4.8) -(C ₁ -C ₆ )-Alkyl, wherein the alkyl group is unsubstituted or substituted once, twice or three times by halogen, 4.9) -O-(C ₁ -C ₆ )-Alkyl, wherein the alkyl group is unsubstituted or substituted once, twice or three times by halogen, 4.10) pyridyl, or 4.11) Phenyl, wherein phenyl is unsubstituted or substituted once independently of each other by a group selected from halogen, -(C ₁ -C ₆ )-alkoxy and -(C ₁ -C ₆ )-alkyl , two or three times, and R4 and R5 or R5 and R6 together with the benzene ring and the carbon atom to which they are attached in each case form independently of each other a group selected from benzo[1,4]dioxane, 2,3-dihydrobenzofuran and In the ring system of 2,2-difluorobenzo[1,3]dioxole, the other groups R3, R6 and R7 or R3, R4 and R7 are hydrogen atoms. 3. A compound of formula I according to claim 1 or 2, wherein For case a), R1 is a hydrogen atom, R2 is -(C ₁ -C ₃ )-alkyl, wherein the alkyl is substituted by the following substituents: 1. Phenyl, wherein phenyl is substituted one, two or three times independently of each other by the following substituents: 1.1) _-CH2 -C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl, propyl or butyl, 1.2)-(C ₀ -C ₆ )-alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 are hydrogen, methyl, ethyl, propyl or butyl, or R9 and R10 together with the nitrogen atom to which they are attached form a group derived from: pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, morpholine, isothiazole Alkane or thiomorpholine, in the case of nitrogen, the nitrogen atoms can independently of one another be unsubstituted or substituted by (C ₁ -C ₄ )-alkyl, 1.3)-(C ₀ -C ₄ )-Alkyl-C(O)-NH-CN, 1.4)-O-(C ₀ -C ₆ )-alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the meanings described in 1.2) above, 1.5)-(C ₀ -C ₆ )-Alkyl-C(O)-N(R8)-(C ₀ -C ₆ )-Alkyl-N(R9)-(R10), wherein R8, R9 and R10 has the meaning stated above, 1.6)-C(O)-N(R8)-(C ₀ -C ₂ )-Alkyl-Het, wherein R8 has the above-mentioned meanings, Het is azepine, azetidine, azetidine Propane, benzimidazole, benzofuran, benzo[1,4]dioxin, 1,3-benzodioxole, 4H-benzo[1,4]oxazine, benzox Azole, benzothiazole, benzothiophene, quinazolidine, quinoline, quinoxaline, chroman, cinnoline, 1,2-diazepine, 1,3-diazepine, 1 , 4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, Isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, ethylene oxide, piperazine, piperidine, phthalazine, pyran , pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1, 4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3- Triazole or 1,2,4-triazole, and Het is unsubstituted or substituted one, two or three times independently of each other by the following substituents: a) halogen, b) cyano, c) nitro, d) hydroxyl, e) amino groups, f)-C(O)-O-(C ₁ -C ₄ )-alkyl, g)-C(O)-OH, h)-(C ₁ -C ₄ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, i) -O-(C ₁ -C ₄ )-Alkyl, wherein the alkyl group is unsubstituted or substituted once, twice or three times by halogen, or 1.7)-C(O)-N(R8)-(C ₀ -C ₄ )-alkyl-phenyl, wherein phenyl is unsubstituted or independently of one another by the groups a) to i) mentioned above instead of once, twice or thrice, 1.8) -CH ₂ -N(R9)-(R10), wherein R9 and R10 have the meanings stated above, 1.9) -(CH ₂ ) _y -N(R8)-C(O)-(C ₁ -C ₄ )-Alkyl, wherein the alkyl groups are unsubstituted or independently of one another by the groups mentioned above a) to i) substitution once, twice or three times and y is 1 or 2, 1.10) -(CH ₂ ) _x -N(R8)-C(O)-(C ₀ -C ₂ )-alkyl-phenyl, wherein phenyl is unsubstituted or independently of each other by the above-mentioned groups Groups a) to i) are substituted once, twice or three times and x is 0, 1 or 2, 1.11) -(CH ₂ ) _x -N(R8)-C(O)-(C ₀ -C ₂ )-alkyl-Het, wherein Het is unsubstituted or independently of each other by the above-mentioned groups a ) to i) are substituted once, twice or three times and x is 0, 1 or 2, 1.12) -(CH ₂ ) _x -N(R8)-C(O)-O-(C ₁ -C ₄ )-Alkyl, wherein the alkyl group is unsubstituted or independently of each other by the groups mentioned above a) to i) are substituted once, twice or three times and x is 0, 1 or 2, 1.13) -(CH ₂ ) _x -N(R8)-C(O)-O-(C ₀ -C ₄ )-alkyl-phenyl, wherein phenyl is unsubstituted or independently of each other mentioned above The groups a) to i) of are substituted once, twice or three times and x is 0, 1 or 2, 1.14) -(CH ₂ ) _x -N(R8)-C(O)-O-(C ₀ -C ₄ )-alkyl-Het, wherein Het is unsubstituted or independently of each other by the above-mentioned groups Groups a) to i) are substituted once, twice or three times and x is 0, 1 or 2, 1.15)-( _CH2 ) _x -N(R8)-C(O)-N(R11)-R12, wherein R8 and x have the meanings stated above, R11 and R12 are identical or different and independently of each other: 1.15.1) Hydrogen, 1.15.2) methyl, ethyl, propyl or butyl, 1.15.3) -(C ₀ -C ₂ )-alkyl-phenyl, wherein phenyl is unsubstituted or substituted independently of one another once, twice or three times by the groups a) to i) mentioned above, 1.15.4)-(C ₀ -C ₂ )-Alkyl-Het, wherein Het is unsubstituted or substituted independently of each other once, twice or three times by the groups a) to i) mentioned above, 1.15.5)-C(O)-(C ₁ -C ₄ )-alkyl, 1.15.6)-C(O)-(C ₀ -C ₂ )-alkyl-phenyl, 1.15.7)-C(O)-(C ₀ -C ₂ )-alkyl-Het, 1.15.8) -SO ₂ -(C ₁ -C ₄ )-alkyl, 1.15.9) -SO ₂ -(C ₀ -C ₄ )-alkyl-phenyl, or 1.15.10) -SO ₂ -(C ₀ -C ₂ )-alkyl-Het, R3, R4, R5, R6 and R7 are identical or different and independently of each other are: 1. Hydrogen atom, 2. Halogen, 3. -(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, 4. -O-(C ₁ -C ₆ )-Alkyl, wherein alkyl is unsubstituted or substituted once, twice or three times by halogen, or R4 and R5 or R5 and R6 together with the carbon atoms they are connected independently form dioxane, dioxole, dihydrofuran or furan ring, other groups R3, R6 and R7 or R3, R4 and R7 have the meanings of 1. to 4. mentioned above, or for case b), R1 is a hydrogen atom, R2 is -(C ₁ -C ₂ )-alkyl, wherein the alkyl is substituted once, twice or three times by the following substituents: 1.-C(O)-O-R8', wherein R8' is 1.1) hydrogen atom or 1.2) -(C ₁ -C ₂ )-Alkyl, 2. Phenyl, wherein phenyl is substituted one, two or three times independently of each other by the following substituents: 2.1) -O-(C ₂ -C ₄ )-Alkyl-N(R9')-R10', wherein R9' and R10' are independently hydrogen, methyl or ethyl, or R9' and R10' and The nitrogen atoms to which they are attached together form a group which can be derived from: pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, in the case of piperazine the second nitrogen atom can be replaced by methyl or ethyl substitution, 2.2) -O-(C ₁ -C ₂ )-alkyl-C(O)-O-R8', wherein R8' are independently hydrogen, methyl or ethyl, or 2.3) -N(R14)-(R15), wherein R14 and R15 together with the nitrogen atom to which they are attached form a group derivable from: pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazole Alkane, piperazine, isoxazolidine, morpholine, isothiazolidine or thiomorpholine, in the case of nitrogen, the nitrogen atoms may independently of one another be unsubstituted or substituted by methyl or ethyl, 2.4) -(CH ₂ ) _k -N(R9')-(R10'), wherein k is 2, 3 or 4, R9' and R10' are identical or different and independently of each other are hydrogen, methyl or ethyl, Or R9' and R10' together with the nitrogen atom to which they are attached form a group which may be derived from: pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, in the case of piperazine, the second nitrogen atoms may be substituted by methyl or ethyl, and R4 and R5 or R5 and R6 together with the benzene ring and the carbon atom to which they are attached in each case independently form one another selected from the group consisting of benzo[1,4]dioxane, 2,3-dihydrobenzofuran and 2 , the ring system of 2-difluorobenzo[1,3]dioxole, and the other groups R3, R6 and R7 or R3, R4 and R7 are hydrogen atoms. 4. A compound of formula I as claimed in one or more of claims 1 to 3, which is selected from one of the following compounds: Pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-(4-propylcarbamoylbenzylamide), Pyrimidine-4,6-carboxylic acid 4-(4-isopropylcarbamoylbenzylamide) 6-(3-methoxybenzylamide), [4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoisopropyl ester, Pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-[(2-phenoxyethyl)amide], (5-{[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}pentyl)carboxyaminomethyl ester, Pyrimidine-4,6-carboxylic acid 4-[4-(2-dimethylaminoethylcarbamoyl)benzylamide]6-(3-methoxybenzylamide), Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[4-(2-dimethylaminoethyl Carbamoyl) benzylamide], Pyrimidine-4,6-carboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-dimethylaminoethylcarbamoyl)benzylamide], Pyrimidine-4,6-carboxylic acid 4-dimethylcarbamoylmethylamide 6-(3-methoxybenzylamide), [4-({[6-(3-aminobenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyamino tert-butyl ester, Pyrimidine-4,6-dicarboxylic acid 4-(3-chlorobenzylamide) 6-(4-fluoro-3-methylbenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-[(2-chloropyridin-4-ylmethyl)amide] 6-(4-fluoro-3-methylbenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-benzylamide 6-(4-fluoro-3-methylbenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[(pyridin-4-ylmethyl)amide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-(pyridin-3-ylmethyl)amide], Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl] benzylamide}, Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-yl-2-oxoethoxy)benzylamide], Pyrimidine-4,6-carboxylic acid 4-(4-diethylcarbamoylmethoxybenzylamide) 6-(4-fluoro-3-methylbenzylamide), Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(isopropylcarbamoylmethyl)benzylamide], Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[(2-morpholin-4-ylethylcarbamoyl)methyl]benzylamide} , Pyrimidine-4,6-carboxylic acid 4-(4-diethylcarbamoylmethylbenzylamide) 6-(4-fluoro-3-methylbenzylamide), Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-yl-2-oxoethyl)benzylamide], Pyrimidine-4,6-carboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(isopropylcarbamoylmethoxy)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[(pyridin-3-ylmethyl)amide], Pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-({[(pyridin-4-ylmethyl)carbamoyl]methyl}amide), Pyrimidine-4,6-carboxylic acid 4-({[(2-chloropyridin-4-ylmethyl)carbamoyl]-methyl}amide) 6-(3-methoxybenzylamide), Pyrimidine-4,6-carboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-({[(2-chloropyridin-4-ylmethyl)carbamoyl]methyl}amide), [4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoisobutyl ester, [4-({[6-(3-Methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoethyl ester, 4-({[6-(3-Methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoallyl ester, Pyrimidine-4,6-carboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(1-methylpiperidin-3-yloxy)benzylamide], Pyrimidine-4,6-carboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-({[(pyridin-3-ylmethyl)carbamoyl]methyl}amide), Pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide], Pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)benzylamide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[(2′-sulfamoylbiphenyl-2 -ylmethyl) amides], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(thiophen-2-ylmethyl)amide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(5-methylfuran-2-ylmethyl)amide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(5-methylfuran-2-ylmethyl)amide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(5-pyridin-2-ylthiophen-2-ylmethyl)amide] , Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(pyridin-3-ylmethyl)amide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[(pyridin-3-ylmethyl)amide] , Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[(5-methylfuran-2-ylmethyl) base) amides], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[(thiophen-2-ylmethyl)amide] , Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(5-methylisoxazol-3-ylmethyl)amide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(1-methyl-1H-pyrazol-4-ylmethyl)amide ], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(2,5-dimethylfuran-3-ylmethyl)amide] , Pyrimidine-4,6-carboxylic acid 4-[(6-aminopyridin-3-ylmethyl)amide] 6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(1-methyl-1H-pyrrol-2-ylmethyl)amide] , Pyrimidine-4,6-carboxylic acid 4-[(1H-benzimidazol-2-ylmethyl)amide]6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[(pyrazin-2-ylmethyl)amide], Pyrimidine-4,6-carboxylic acid 4-[(2,2-difluorobenzo[1,3]dioxol-5-ylmethyl)amide]6-[(pyridin-4-ylmethyl) base) amides], Methyl ({6-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)carbamoyl]pyrimidine-4-carbonyl}amino)acetate, Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(2-methyl-1H-imidazol-4-ylmethyl)amide] , Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[(2-pyridin-2-ylethyl)amide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-{[3-(4-fluorophenyl)-1H-pyrazole-4- base methyl] amides}, Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[4-(3-dimethylaminopropoxy base) benzylamide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[4-(2-dimethylaminoethoxy base) benzylamide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]6-[3-(2-dimethylaminoethoxy base) benzylamide], Pyrimidine-4,6-carboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[(pyridin-4-ylmethyl)amide], Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-(4-[3′-methylsulfonyl]ureidobenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(4-oxopiperidine-1-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(4-oxopiperidine-1-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(4-oxopiperidine-1-carbonyl)benzylamide ], Pyrimidine-4,6-dicarboxylic acid 4-[4-(4-hydroxypiperidine-1-carbonyl)benzylamide]6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(4-hydroxypiperidine-1-carbonyl)benzylamide] , Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(4-hydroxypiperidine-1-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(thiomorpholine-4-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(3-oxopiperazine-1-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(3-oxopiperazine-1-carbonyl)benzylamide ], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(3-oxopiperazine-1-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(2-hydroxyethylcarbamoyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-hydroxyethylcarbamoyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide}, Pyrimidine-4,6-dicarboxylic acid 4-(4-cyanocarbamoylbenzylamide) 6-(4-fluoro-3-methylbenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(3-morpholin-4-ylpropylcarbamoyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(3-morpholin-4-yl-propylcarbamoyl ) benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(4-methylpiperazine-1-carbonyl)benzylamide], Pyrimidine-4,6 dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-{4-[(pyridin-4-ylmethyl)carbamoyl]benzyl amides}, Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-(4-[3′-methylsulfonyl]ureidobenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-(4-[3-methylsulfonyl]ureidobenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide], Pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-(3-[3′-methylsulfonyl]ureidobenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(4-hydroxycarbamoylbenzylamide) 6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(hydroxycarbamoylmethylcarbamoyl)benzylamide] , Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(1-methylpiperidin-3-yloxy)benzyl base amides], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-piperazin-1-ylethylcarbamoyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-(4-hydroxycarbamoylbenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-(4-hydroxycarbamoylbenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(1-methylpiperidin-3-yloxy)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-tert-butylcarbamoylbenzylamide) 6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[methyl-(1-methylpiperidin-4-yl)carbamoyl]benzylamide}, {4-[({6-[(2,3-Dihydrobenzofuran-5-ylmethyl)carbamoyl]pyrimidine-4-carbonyl}amino)methyl]benzoylamino}acetic acid, Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-{4-[4-(2-dimethylaminoethyl)piperazine-1-carbonyl]benzylamide}6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-(4-[3′-methylsulfonyl]ureidobenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[3-(2-morpholin-4-ylethylcarbamoyl)benzylamide], [4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)benzoylamino]acetic acid, Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-piperazin-1-ylacetylamino)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-yl-ethylcarbamoyl)benzylamide], Methyl [4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)benzoylamino]acetate, Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[3-(morpholine-4-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3 -methoxybenzylamide) 6-{4-[(piperidin-4-ylmethyl)carbamoyl]benzylamide}, Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(piperidin-4-ylcarbamoyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(piperidin-4-ylcarbamoyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[methyl-(1-methylpiperidin-4-yl)carbamoyl]benzyl amides}, Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine -7-ylmethyl)amide], Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[(piperidin-4-ylmethyl)carbamoyl]benzylamide}, Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(4-methylpiperazine-1-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(4-pyridin-4-ylpiperazine-1-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-morpholin-4-ylacetylamino)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(morpholine-4-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-(4-[p-toluenesulfonyl]ureidobenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]6-[4-(4-methylpiperazine-1-carbonyl)benzyl amides], Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl ) benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-(4-[3′-phenylsulfonyl]ureidobenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(2-morpholin-4-yl-ethylcarbamoyl ) benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(2-pyrrolidin-1-ylethoxy)benzyl amides], Pyrimidine-4,6-dicarboxylic acid 4-[4-(3-cyclohexanecarbonylureido)benzylamide]-6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[3-(pyridine-3-carbonyl)ureido]benzylamide}, Pyrimidine-4,6-dicarboxylic acid 4-[4-(3-isobutyrylureido)benzylamide]6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-pyrrolidin-1-ylacetylamino)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-[(4-chlorothiophen-2-ylmethyl)amide]6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[2-(2-oxo-pyrrolidin-1-yl)acetylamino]benzylamide}, Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-methyl)amide]6-[(thiophen-3-ylmethyl)amide], Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(3-methylthiophen-2-ylmethyl)amide], Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[(5-methylthiophen-2-ylmethyl)amide], Pyrimidine-4,6-dicarboxylic acid 4-[4-(2-dimethylaminoacetylamino)benzylamide]6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide]6-[4-(2-morpholin-4-ylethoxy)benzyl amides], Pyrimidine-4,6-dicarboxylic acid 4-[4-(3-cyclohexylureido)benzylamide]6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-{4-[3-(2,6-dichloropyridin-4-yl)ureido]benzylamide} 6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-[4-(3-tert-butylureido)benzylamide]6-(3-methoxybenzylamide), [4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminobut-2-ynyl ester, Pyrimidine-4,6-dicarboxylic acid 4-(4-ethanesulfonylaminobenzylamide) 6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(thiophene-2-sulfonylamino)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2,2,2-trifluoroethanesulfonylamino)benzylamide], [4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminomethyl ester, [4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoprop-2-ynyl ester, [4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyamino 2-methoxyethyl ester, [4-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyamino 4-fluorophenyl ester, Pyrimidine-4,6-dicarboxylic acid 4-[4-(3-benzoylureido)benzylamide]6-(3-methoxybenzylamide), [3-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminobut-2-ynyl ester, [3-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoprop-2-ynyl ester, [3-({[6-(3-methoxybenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]carboxyaminoisopropyl ester, Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-pyrrolidin-1-ylethylcarbamoyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide}, Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-(4-diethylcarbamoylbenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-{4-[2-(2,6-dimethylpiperidin-1-yl)-2-oxo-ethyl]benzylamide} 6-(4-fluoro -3-methylbenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(1-methylpiperidin-3-yloxy)benzylamide], Pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methoxybenzylamide), Pyrimidine-4,6-dicarboxylic acid 4-[(2-chloropyridin-4-ylmethyl)amide]6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide], Pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-(4-methanesulfonylaminobenzylamide) or Pyrimidine-4,6-dicarboxylic acid 4-(4-methanesulfonylbenzylamide) 6-(3-methoxybenzylamide). 5. A process for the preparation of a compound of formula I according to one or more of claims 1 to 4, wherein the compound of formula II

a) react with formula IIIa or IIIb compound wherein R1, R2, R3, R4, R5, R6 and R7 have the meanings given in formula I and Y is halogen, hydroxyl or _C1 - _C4 -alkoxy, or together with carbonyl forms active esters or mixed anhydrides, To form a compound of formula I, if desired, the reaction product can be converted into its physiologically tolerable salt, or b) reacting the compound of formula II with the compound of formula IIIa or IIIb to obtain the compound of formula IVa or IVb

wherein R1 to R7 have the meanings given in formula I and Y is halogen, hydroxy or _C1 - _C4 -alkoxy, or together with a carbonyl group forms active esters or mixed anhydrides, where necessary, the compound of formula IVa or IVb is purified, Compounds of formula Ilia or IIIb are then used to convert to compounds of formula I. 6. A medicament comprising an effective amount of at least one compound of formula I according to one or more of claims 1 to 4 and pharmaceutically acceptable and physiologically tolerable carrier substances, additives and/or or other active compounds and auxiliary substances. 7. Use of compounds of formula I as claimed in one or more of claims 1 to 4 for the preparation of medicaments for the prophylaxis and treatment of diseases in which an increased activity of matrix metalloproteinase 13 is involved. 8. The use as claimed in claim 7, wherein the disease in which an increased activity of matrix metalloproteinase 13 is involved is a degenerative joint disease such as osteoarthrosis, spondylosis or after joint trauma or meniscal injury or kneecap injury or Cartilage loss following ligamentous ruptures after relatively prolonged arthrodesis, they also include diseases of connective tissue such as collagen diseases, periodontal disease, wound healing disorders and chronic diseases of the locomotor organs such as inflammatory, immunologically determined or metabolic Determined acute and chronic arthritis, arthrosis, myalgia and bone metabolic disorders or cancerous diseases such as breast cancer.