Benzylic oxindole pyrimidines
The present invention encompasses compounds of general formula (I) wherein the groups R 5 to R 10 , A, L 1 , B, m and p are defined as in claim 1 , which are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation, pharmaceutical preparations which contain such compounds and their use as medicaments.
1. A compound of the formula (I)
wherein
R 5 is selected from among trifluoromethyl and halogen;
R 6 , R 7 and R 8 are independently selected in each case from among hydrogen and C 1-4 alkyl or
R 6 and R 7 together with the carbon atom to which they bond form a saturated, 3-5 membered hydrocarbon ring;
ring system A is selected from among C 6-10 aryl, 3-14 membered heterocyclyl and 5-12 membered heteroaryl;
each R 9 is independently selected in each case from among C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen and —CN;
m denotes 0, 1, 2 or 3;
L 1 is selected from among a bond, —(CH 2 ) n —O, —(CH 2 ) n —NH, —(CH 2 ) n —NH—C(O), —(CH 2 ) n —C(O)—NH, —(CH 2 ) n — and —(CH 2 ) n —C(O), while in the present nomenclature the linker group L 1 on the right binds to the ring system A;
n denotes 0, 1, 2 or 3;
ring system B is selected from among 4-10 membered, saturated or unsaturated heterocyclyl and phenyl;
each R 10 is independently selected in each case from among R a and R b ;
p denotes 0, 1, 2 or 3;
each R a independently denotes a group optionally substituted by one or more identical or different R b and/or R c selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;
each R b is independently selected in each case from among —OR c , —SR c , —NR c R c , halogen, —CN, —NO 2 , —C(O)R c , —C(O)OR c , —C(O)NR c R c , —C(NR f )NR c R c , —OC(O)R c , —OC(O)OR c , —S(O) 2 R c , —S(O) 2 NR c R c , —NR f C(O)R c , —NR f C(O)OR c , —NR f C(O)NR c R c , —NR f C(NR f )NR c R c and —NR f S(O) 2 R c , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R c independently denotes hydrogen or a group optionally substituted by one or more identical or different R d and/or R e selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;
each R d is independently selected in each case from among —OR e , —SR e , —NR e R e , halogen, —CN, —NO 2 , —C(O)R e , —C(O)OR e , —C(O)NR e R e , —C(NR f )NR e R e , —OC(O)R e , —OC(O)OR e , —S(O) 2 R e , —S(O) 2 NR e R e , —NR f C(O)R e , —NR f C(O)OR e , —NR f C(O)NR e R e , —NR f C(NR f )NR e R e and —NR f S(O) 2 R e , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R e independently denotes hydrogen or a group optionally substituted by one or more identical or different R f selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and
each R f is independently selected in each case from among hydrogen and C 1-6 alkyl,
while the compounds (I) may optionally also occur in the form of their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or as the respective salts of all the above-mentioned forms.
2. The compound according to claim 1 , wherein
R 5 denotes trifluoromethyl.
3. The compound according to claim 1 , wherein
R 5 denotes chlorine.
4. The compound according to claim 1 , wherein
R 5 denotes bromine.
5. The compound according to claim 1 , wherein
R 6 and R 7 in each case denote methyl and R 8 denotes hydrogen.
6. The compound according to claim 1 , wherein
R 6 , R 7 and R 8 in each case denote hydrogen.
7. The compound according to claim 1 , wherein
R 6 and R 7 together with the carbon atom to which they bond form a cyclopropyl ring and
R 8 denotes hydrogen.
8. The compound according to claim 1 , wherein
ring system A is selected from among phenyl and 5-6 membered heteroaryl.
9. The compound according to claim 8 , wherein
ring system A is a phenyl.
10. The compound according to claim 8 , wherein
ring system A is a 5-6 membered, nitrogen-containing heteroaryl.
11. The compound according to claim 10 , wherein
ring system A is a pyridyl or pyrazolyl.
12. The compound according to claim 1 , wherein
m has the value 0.
13. The compound according to claim 1 , wherein
m has the value 1 or 2 and
R 9 is selected from among halogen, C 1-4 alkyl and C 1-4 alkoxy.
14. The compound according to claim 13 , wherein
m has the value 1 or 2 and
R 9 is selected from among C 1-4 alkyl and C 1-4 alkoxy.
15. The compound according to claim 14 , wherein
m has the value 1 or 2 and
R 9 is selected from among methyl, ethyl, methoxy and ethoxy.
16. The compound according to claim 1 , wherein
ring system A and the m groups R 9 together denote
R 9a is selected from among hydrogen, C 1-4 alkyl and C 1-4 alkoxy and
R 9b is selected from among hydrogen and C 1-4 alkyl.
17. The compound according to claim 16 , wherein
ring system A and the m groups R 9 together denote
R 9a is selected from among hydrogen, methyl, ethyl, methoxy and ethoxy and
R 9b is selected from among hydrogen, methyl and ethyl.
18. The compound according to claim 1 , wherein
ring system A and the m groups R 9 together denote
19. The compound according to claim 1 , wherein
L 1 is selected from among a bond, —(CH 2 ) 2 —O, —NH—C(O), —C(O)—NH— and —C(O), while in the present nomenclature the linker group L 1 on the right binds to the ring system A.
20. The compound according to claim 19 , wherein
L 1 corresponds to a bond.
21. The compound according to claim 19 , wherein
L 1 is selected from among —(CH 2 ) 2 —O, —NH—C(O)— and —C(O)—.
22. The compound according to claim 1 , wherein
ring system B is a 4-10 membered, saturated or unsaturated heterocyclyl.
23. The compound according to claim 22 , wherein
ring system B is a 5-7 membered, saturated and nitrogen-containing heterocyclyl.
24. The compound according to claim 23 , wherein
ring system B is selected from among piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl and 2,5-diaza-bicyclo[2,2,1]heptyl.
25. The compound according to claim 1 , wherein
p has the value 0.
26. The compound according to claim 1 , wherein
p has the value 1 or 2,
each R 10 is independently selected in each case from among R a and R b ;
each R a independently denotes a group optionally substituted by one or more identical or different R b and/or R c selected from among C 1-6 alkyl, C 3-10 cycloalkyl and 3-14 membered heterocyclyl;
each R b is independently selected in each case from among —OR c , —NR c R c , halogen, —CN, —C(O)R c , —C(O)OR c , —C(O)NR c R c , —S(O) 2 R c and —S(O) 2 NR c R c , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R c independently denotes hydrogen or a group optionally substituted by one or more identical or different R d and/or R e selected from among C 1-6 alkyl, C 3-10 cycloalkyl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;
each R d is independently selected in each case from among —OR e , —NR e R e , —CN, —C(O)R e , —C(O)OR e and —NR f C(O)OR e , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R e independently denotes hydrogen or a group optionally substituted by one or more identical or different R f selected from among C 1-6 alkyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and
each R f is independently selected in each case from among hydrogen and C 1-6 alkyl.
27. The compound according to claim 1 , wherein
p has the value 1 or 2,
each R 10 is independently selected in each case from among R a and R b ;
each R a independently denotes a group optionally substituted by one or more identical or different R b and/or R c selected from among C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocyclyl;
each R b is independently selected in each case from among —OR c , —NR c R c , halogen, —CN, —C(O)R c , —C(O)OR c , —C(O)NR c R c , —S(O) 2 R c and —S(O) 2 NR c R c , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R c independently denotes hydrogen or a group optionally substituted by one or more identical or different R d and/or R e selected from among C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl;
each R d is independently selected in each case from among —OR e , —NR e R e , —CN, —C(O)R e , —C(O)OR e and —NR f C(O)OR e , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R e independently denotes hydrogen or a group optionally substituted by one or more identical or different R f selected from among C 1-6 alkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl, and
each R f is independently selected in each case from among hydrogen and C 1-6 alkyl.
28. The compound according to one of claims 1 , 26 or 27 , wherein
p has the value 1.
29. The compound according to claim 1 , wherein
ring system B and the p groups R 10 together denote
each R 10 is independently selected in each case from among R a and R b ;
each R a independently denotes a group optionally substituted by one or more identical or different R b and/or R c selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;
each R b is independently selected in each case from among —OR c , —SR c , —NR c R c , halogen, —CN, —NO 2 , —C(O)R c , —C(O)OR c , —C(O)NR c R c , —C(NR f )NR c R c , —OC(O)R c , —OC(O)OR c , —S(O) 2 R c , —S(O) 2 NR c R c , —NR f C(O)R c , —NR f C(O)OR c , —NR f C(O)NR c R c , —NR f C(NR f )NR c R c and —NR f S(O) 2 R c , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R c independently denotes hydrogen or a group optionally substituted by one or more identical or different R d and/or R e selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;
each R d is independently selected in each case from among —OR e , —SR e , —NR e R e , halogen, —CN, —NO 2 , —C(O)R e , —C(O)OR e , —C(O)NR e R e , —C(NR f )NR e R e , —OC(O)R e , —OC(O)OR e , —S(O) 2 R e , —S(O) 2 NR e R e , —NR f C(O)R e , —NR f C(O)OR e , —NR f C(O)NR e R e , —NR f C(NR f )NR e R e and —NR f S(O) 2 R e , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R e independently denotes hydrogen or a group optionally substituted by one or more identical or different R f selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and
each R f is independently selected in each case from among hydrogen and C 1-6 alkyl.
30. The compound according to claim 29 , wherein
ring system B and the p groups R 10 together denote
each R 10 is independently selected in each case from among R a and R b ;
each R a independently denotes a group optionally substituted by one or more identical or different R b and/or R c selected from among C 1-6 alkyl, C 3-10 cycloalkyl and 3-14 membered heterocyclyl;
each R b is independently selected in each case from among —OR c , —NR c R c , halogen, —CN, —C(O)R c , —C(O)OR c , —C(O)NR c R c , —S(O) 2 R c and —S(O) 2 NR c R c , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R c independently denotes hydrogen or a group optionally substituted by one or more identical or different R d and/or R e selected from among C 1-6 alkyl, C 3-10 cycloalkyl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;
each R d is independently selected in each case from among —OR e , —NR e R e , —CN, —C(O)R e , —C(O)OR e and —NR f C(O)OR e , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R e independently denotes hydrogen or a group optionally substituted by one or more identical or different R f selected from among C 1-6 alkyl, C 6-10 aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and
each R f is independently selected in each case from among hydrogen and C 1-6 alkyl.
31. The compound according to claim 30 , wherein
ring system B and the p groups R 10 together denote
each R 10 is independently selected in each case from among R a and R b ;
each R a independently denotes a group optionally substituted by one or more identical or different R b and/or R c selected from among C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocyclyl;
each R b is independently selected in each case from among —OR c , —NR c R c , halogen, —CN, —C(O)R c , —C(O)OR c , —C(O)NR c R c , —S(O) 2 R c and —S(O) 2 NR c R c , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R c independently denotes hydrogen or a group optionally substituted by one or more identical or different R d and/or R e selected from among C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl;
each R d is independently selected in each case from among —OR e , —NR e R e , —CN, —C(O)R e , —C(O)OR e and —NR f C(O)OR e , as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems;
each R e independently denotes hydrogen or a group optionally substituted by one or more identical or different R f selected from among C 1-6 alkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl, and
each R f is independently selected in each case from among hydrogen and C 1-6 alkyl.
32. The compound according to claim 1 , wherein
ring system B and the p groups R 10 together denote
each R 10 is independently selected in each case from among —C(O)—C 1-4 alkyl, hydrogen, C 1-6 alkyl (CN), C 1-6 haloalkyl —C(O)—O—C 1-4 alkyl, —COOH, (C 1-4 alkyl) 2 N—C 1-4 alkylene-C(O), (C 1-4 alkyl)NH—C 1-4 alkylene-C(O), H 2 N—C 1-4 alkylene-C(O), HO—C 1-4 alkylene-C(O), —C(O)—N(C 1-4 alkyl) 2 , —C(O)—NH(C 1-4 alkyl), —C(O)NH 2 , C 1-4 alkyl-O—C 1-4 alkylene-C(O), 4-6 membered heterocyclyl (optionally substituted by C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl), C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, HO—C 2-4 alkyl, C 1-4 alkyl-O—C 2-4 alkyl, HO—C 2-4 haloalkyl, C 1-4 alkyl-S(O) 2 , C 1-4 alkyl-NH—C(O)—C 1-4 alkyl, H 2 N—C(O)—C 1-4 alkyl and C 1-4 alkyl-S(O) 2 —C 1-4 alkyl.
33. The compound according to claim 32 , wherein
ring system B and the p groups R 10 together denote
34. The compound according to claim 1 , wherein
ring system B and the p groups R 10 together denote
each R 10 is independently selected in each case from among C 1-4 alkyl-O—C 2-4 alkylene-NH, C 1-4 alkyl-O—C 2-4 alkylene-N(C 1-4 alkyl), HO—C 2-4 alkylene-N(C 1-4 alkyl), HO—C 2-4 alkylene-NH, 4-6 membered heterocyclyl (optionally substituted by C 1-4 alkyl, 3-6 membered heterocyclyl, halogen, —OH, —CN, C 1-4 alkoxy, —N(C 1-4 alkyl) 2 or C 3-6 cycloalkyl), (C 1-4 alkyl) 2 N—C 2-4 alkylene-N(C 1-4 alkyl), (C 1-4 alkyl) 2 N—C 2-4 alkylene-NH, —N(C 1-4 alkyl) 2 , —NH(C 1-4 alkyl), C 1-4 alkyl-NH—C(O)— and (C 1-4 alkyl) 2 N—C(O)—.
35. A compound, or pharmaceutically acceptable salts thereof, selected from among:
36. The compound according to claim 1 wherein the compound is a pharmaceutically acceptable salt thereof.
37. A method of treating a cancer selected from hepatocellular carcinomas (HCC), non-small cell lung cancer (NSCLC), breast cancer and prostate cancer comprising administering to a patient a therapeutically effective amount of a compound according to claim 1 or the pharmaceutically acceptable salts thereof.
38. The method according to claim 37 wherein the patient is a human being.
39. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or the pharmaceutically acceptable salts thereof optionally in combination with conventional excipients and/or carriers.
40. The pharmaceutical composition according to claim 39 and at least one other cytostatic or cytotoxic active substance, different from formula (I) of claim 1 .