5-membered annelated heterocyclic pyrimidines as kinase inhibitors
This invention comprises the novel compounds of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Q 1 , Q 2 , X 1 , X 2 , Y and Z have defined meanings, having cell cycle kinase inhibiting enzymatic activity, their preparation, compositions containing them and their use as a medicine.
1. A compound of formula (I),
a N-oxide, an addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein
X 1 and X 2 are each independently N or CH with the exception that X 1 and X 2 can not be both N;
Q 1 is CH 2 , or N;
Q 2 is CH 2 , N, or O;
n is an integer with value 0 or 1 and when n is 0 then a direct bond is intended;
t is an integer with value 0 or 1 and when t is 0 then a direct bond is intended;
—Y Z— is —CH═N—, —C(═O)—NH—, —N═CH—, —C(═O)—CH 2 —, or —NH—C(═O)—;
ring B represents phenyl, cyclopentyl, cyclohexyl, norbornyl or
L is a direct bond, —(CH 2 ) r —NR 7 —(CH 2 ) s —, —(CR 8 2 ) r —O—(CH 2 ) s —, —C(═O)—, —(CH 2 ) r —O—C(═O)—, —(CH 2 ) r —NR 7 —C(═O)—, —S(═O) 2 —, —(CH 2 ) r —NH—S(═O) 2 —, or —C 1-6 alkyl-; wherein
each —(CH 2 ) r — moiety is linked to ring A;
each s is an integer with value 0 or 1 and when s is 0 then a direct bond is intended;
each r is an integer with value 0, 1, 2 or 3 and when r is 0 then a direct bond is intended;
each R 7 is hydrogen, C 1-6 alkyl or C 1-4 alkyloxycarbonyl;
each R 8 is independently hydrogen, hydroxy or C 1-6 alkyl; or
two R 8 together can form a bivalent radical of formula —CH 2 —CH 2 —;
R 1 , R 2 and R 5 are each independently hydrogen, hydroxy or C 1-6 alkyl;
R 3 is hydrogen, hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkyl, hydroxycyclopropylC 1-6 alkyl, hydroxycyclopropylcarbonyl, hydroxyC 1-6 alkylcarbonyl, hydroxyC 1-6 alkyloxy, C 1-6 alkyloxy, hydroxyC 1-6 alkyloxyC 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkylcarbonyl, C 1-6 alkyloxyC 1-6 alkyloxy, C 1-6 alkyloxyC 1-6 alkyloxyC 1-6 alkyl, pyridinyl, —NR 9 R 10 , or —S(═O) 2 —NR 9 R 10 ;
wherein each R 9 and R 10 independently represent hydrogen, C 1-6 alkyl, C 1-4 alkyloxycarbonyl, hydroxyC 1-6 alkyl, hydroxycyclopropylC 1-6 alkyl or C 1-6 alkyloxyC 1-6 alkyl;
R 4 is hydrogen or halo;
R 6 is hydrogen, C 1-6 alkyl or C 1-4 alkyloxycarbonyl.
2. A compound as claimed in claim 1 wherein X 1 and X 2 are each CH.
3. A compound as claimed in claim 1 wherein
n is 0; t is 0; L is a direct bond, —(CH 2 ) r —NR 7 —(CH 2 ) s —, —C(═O)—, —(CH 2 ) r —NR 7 —C(═O)—, —S(═O) 2 — or —C 1-6 alkyl-; s is 1; r is 0 or 2; each R 7 is hydrogen or C 1-4 alkyloxycarbonyl;
R 1 , R 2 and R 5 are each independently hydrogen; R 3 is hydrogen, hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkyl, hydroxycyclopropylcarbonyl, hydroxyC 1-6 alkylcarbonyl, C 1-6 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkylcarbonyl, pyridinyl, —NR 9 R 10 , or —S(═O)2—NR 9 R 10 ; each R 9 and R 10 independently represent hydrogen, C 1-4 alkyloxycarbonyl or C 1-6 alkyloxyC 1-6 alkyl; and R 6 is hydrogen or C 1-4 alkyloxycarbonyl.
4. A compound as claimed in claim 1 wherein
X 1 and X 2 are each CH; Q 2 is N, or O; n is 0; t is 0; —Y Z— is —N═CH—; ring B represents cyclohexyl or norbornyl; L is a direct bond, —(CH 2 ) r —NR 7 —(CH 2 ) s —, —C(═O)— or —C 1-6 alkyl-; s is 1; r is 0 or 2; each R 7 is hydrogen; R 1 , R 2 and R 5 are each independently hydrogen; R 3 is hydrogen, C 1-6 alkyl or hydroxyC 1-6 alkyl; R 4 is hydrogen; and R 6 is hydrogen.
5. A compound as claimed in claim 1 wherein X 1 and X 2 are each CH; Q 2 is N, or O; n is 0; t is 0; —Y Z— is —N═CH—; ring B represents cyclohexyl or norbornyl; L is a direct bond, —NH—CH 2 —, —C(═O)—or methyl; R 1 , R 2 and R 5 are each independently hydrogen; R 4 is hydrogen; and R 6 is hydrogen.
6. A compound selected from the group consisting of:
Compound No 1
Compound No 2
Compound No 15
Compound No 3
Compound No 60
Compound No 37
Compound No 4
Compound No 23
7. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1 .
8. A process of preparing a pharmaceutical composition wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 1 are mixed.
9. A combination of an anti-cancer agent and a cell cycle kinase inhibitor as claimed in claim 1 .
10. A process for preparing a compound as claimed in claim 1 , said process comprising
a) reacting an intermediate of formula (II) with an intermediate of formula (III) in the presence of a suitable solvent and optionally in the presence of a suitable base, resulting in a compound of formula (I),
b) reacting an intermediate of formula (X), wherein W 1 is a suitable leaving group, with an intermediate of formula (II) in the presence of a suitable solvent, optionally in the presence of a suitable base, resulting in the formation of a compound of formula (I),
c) reacting an intermediate of formula (XIV) with an intermediate of formula (XVI-a) in the presence of a suitable solvent optionally in the presence of a suitable base with the formation of compounds of formula (I) wherein L is —(CH 2 ) r —NH—C(═O)—, herein referred to as compounds of formula (I-a),
d) reacting intermediates of formula (XIV) with intermediates of formula (XVI-b) in the presence of sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence of a suitable acid and in a suitable solvent, resulting in compounds of formula (I) wherein L is —(CH 2 ) r —NH—(CH 2 )—, herein referred to as compounds of formula (I-b), and
and e) cyclizing an intermediate of formula (XXXIII) in the presence of a salt or an acid in a suitable solvent, resulting in compounds of formula (I), wherein —Y Z— is —CH═N—, herein referred to as compounds of formula (I-c)
11. A compound as claimed in claim 2 wherein
n is 0; t is 0; L is a direct bond, —(CH 2 ) r —NR 7 —(CH 2 ) s —, —C(═O)—, —(CH 2 ) r —NR 7 —C(═O)—, —S(═O) 2 — or —C 1-6 alkyl-; s is 1; r is 0 or 2; each R 7 is hydrogen or C 1-4 alkyloxycarbonyl; R 1 , R 2 and R 5 are each independently hydrogen; R 3 is hydrogen, hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkyl, hydroxycyclopropylcarbonyl, hydroxyC 1-6 alkylcarbonyl, C 1-6 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkylcarbonyl, pyridinyl, —NR 9 R 10 , or —S(═O) 2 —NR 9 R 10 ; each R 9 and R 10 independently represent hydrogen, C 1-4 alkyloxycarbonyl or C 1-6 alkyloxyC 1-6 alkyl; and R 6 is hydrogen or C 1-4 alkyloxycarbonyl.
12. A compound as claimed in claim 2 wherein
X 1 and X 2 are each CH; Q 2 is N, or O; n is 0; t is 0; —Y Z— is —N═CH—; ring B represents cyclohexyl or norbornyl; L is a direct bond, —(CH 2 ) r —NR 7 —(CH 2 ) s —, —C(═O)—or —C 1-6 alkyl-; s is 1; r is 0 or 2; each R 7 is hydrogen; R 1 , R 2 and R 5 are each independently hydrogen; R 3 is hydrogen, C 1-6 alkyl or hydroxyC 1-6 alkyl; R 4 is hydrogen; and R 6 is hydrogen.
13. A compound as claimed in claim 3 wherein
X 1 and X 2 are each CH; Q 2 is N, or O; n is 0; t is 0; —Y Z— is —N═CH—; ring B represents cyclohexyl or norbornyl; L is a direct bond, —(CH 2 ) r —NR 7 —(CH 2 ) s —, —C(═O)—or —C 1-6 alkyl-; s is 1; r is 0 or 2; each R 7 is hydrogen; R 1 , R 2 and R 5 are each independently hydrogen; R 3 is hydrogen, C 1-6 alkyl or hydroxyC 1-6 alkyl; R 4 is hydrogen; and R 6 is hydrogen.
14. A compound as claimed in claim 2 wherein X 1 and X 2 are each CH; Q 2 is N, or O; n is 0; t is 0; —Y Z— is —N═CH—; ring B represents cyclohexyl or norbornyl; L is a direct bond, —NH—CH 2 —, —C(═O)—or methyl; R 1 , R 2 and R 5 are each independently hydrogen; R 4 is hydrogen; and R 6 is hydrogen.
15. A compound as claimed in claim 3 wherein X 1 and X 2 are each CH; Q 2 is N, or O; n is 0; t is 0; —Y Z— is —N═CH—; ring B represents cyclohexyl or norbornyl; L is a direct bond, —NH—CH 2 —, —C(═O)—or methyl; R 1 , R 2 and R 5 are each independently hydrogen; R 4 is hydrogen; and R 6 is hydrogen.
16. A compound as claimed in claim 4 wherein X 1 and X 2 are each CH; Q 2 is N, or O; n is 0; t is 0; —Y Z— is —N═CH—; ring B represents cyclohexyl or norbornyl; L is a direct bond, —NH—CH 2 —, —C(═O)—or methyl; R 1 , R 2 and R 5 are each independently hydrogen; R 4 is hydrogen; and R 6 is hydrogen.
17. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 6 .
18. A process of preparing a pharmaceutical composition wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 6 are mixed.
19. A combination of an anti-cancer agent and a cell cycle kinase inhibitor as claimed in claim 6 .