5-phenylthiazole derivatives and use as Pi3 kinase inhibitors
Compounds of formula I in free or salt form, wherein R 1 , R 2 , R 3 , R 4 and R 5 have the meanings as indicated in the specification, are useful for treating diseases mediated by phosphatidylinositol 3-kinase. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
1. A compound of formula I
in free or salt form, wherein
R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by the group consisting of, hydroxy, C 1 -C 8 -alkylamino, carboxy, C 1 -C 8 -alkoxycarbonyl, nitrile, phenyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkyl optionally substituted by hydroxy, C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy optionally substituted by hydroxy, phenyl substituted by hydroxy or C 1 -C 8 -alkyl and, 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that heterocyclic ring being optionally substituted by hydroxy, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy,
R 2 is C 1 -C 3 -alkyl or halogen;
R 5 is hydrogen or halogen;
R 3 is hydrogen, hydroxy, amino, —SOR 8 , —SO 2 R 8 , —SO 2 NH 2 , —SO 2 NR 9 R 10 , —COR 8 , —CONHR 8 , —NHSO 2 R 8 , nitrile, carboxy, —OR 8 or C 1 -C 8 -haloalkyl;
R 4 is —NR 12 R 13 ;
R 8 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by halogen, hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino;
R 9 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl;
R 10 is hydrogen or C 1 -C 8 -alkyl; or
R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl; and
R 12 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl.
2. A compound according to claim 1 wherein
R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by the group consisting of hydroxy, carboxy, C 1 -C 8 -alkoxycarbonyl, nitrile, phenyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy optionally substituted by hydroxy, and a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl,
R 2 is C 1 -C 3 -alkyl;
R 5 is hydrogen or halogen;
R 3 is hydrogen, hydroxy, amino, —SO 2 R 8 , —SO 2 NH 2 , —SO 2 NR 9 R 10 , —NHSO 2 R 8 , cyano, carboxy, —OR 8 or C 1 -C 4 -haloalkyl;
R 4 is —NR 12 R 13 ;
R 8 is C 1 -C 8 -alkyl;
R 9 is C 1 -C 8 -alkyl optionally substituted by hydroxy, C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl;
R 10 is hydrogen or C 1 -C 8 -alkyl; or
R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl; and
R 12 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl.
3. A compound according to claim 2 , in free or salt form, wherein
R 1 is C 1 -C 4 -alkylcarbonyl optionally substituted by the group consisting of hydroxy, carboxy, C 1 -C 4 -alkoxycarbonyl, nitrile, phenyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkyl optionally substituted by hydroxy, C 1 -C 4 -alkoxy optionally substituted by hydroxy, and a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that heterocyclic ring being optionally substituted by C 1 -C 4 -alkyl,
R 2 is C 1 -C 3 -alkyl;
R 5 is hydrogen or halogen;
R 3 is hydrogen, hydroxy, amino, SO 2 R 8 , SO 2 NH 2 , SO 2 NR 9 R 10 , NHSO 2 R 8 , cyano, carboxy, OR 8 or C 1 -C 4 -haloalkyl;
R 4 is —NR 12 R 13 ;
R 8 is C 1 -C 4 -alkyl;
R 9 is C 1 -C 4 -alkyl optionally substituted by hydroxy, C 3 -C 5 -cycloalkyl optionally substituted by hydroxy, C 1 -C 4 -alkoxy, nitrile, di(C 1 -C 4 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 4 -alkyl;
R 10 is hydrogen or C 1 -C 4 -alkyl; or
R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 4 -alkyl; and
R 12 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 4 -alkyl.
4. A compound of formula I according to claim 1 in free or salt form, wherein
R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by the group consisting of hydroxy, C 1 -C 8 -alkylamino, carboxy, C 1 -C 8 -alkyl optionally substituted by the group consisting of hydroxy, C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy optionally substituted by hydroxy, C 1 -C 8 -alkoxycarbonyl, nitrile, or phenyl optionally substituted by hydroxy or C 1 -C 8 -alkyl, and a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that heterocyclic ring being optionally substituted by hydroxy, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy,
R 2 is C 1 -C 3 -alkyl or halogen;
R 5 is hydrogen or halogen;
R 3 is hydrogen, hydroxy, amino, —SOR 8 , —SO 2 R 8 , —SO 2 NH 2 , —SO 2 NR 9 R 10 , —COR 8 , —CONHR 8 , NHSO 2 R 8 , nitrile, carboxy, —OR 8 or C 1 -C 8 -haloalkyl;
R 4 is —NR 12 R 13 ;
R 8 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by halogen, hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino;
R 9 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl;
R 10 is hydrogen or C 1 -C 8 -alkyl; or
R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl; and
R 12 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl.
5. A compound according to claim 4 wherein
R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by the group consisting of hydroxy, carboxy, C 1 -C 8 -alkyl optionally substituted by hydroxy, C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy optionally substituted by hydroxy, C 1 -C 8 -alkoxycarbonyl, nitrile, and phenyl optionally substituted by hydroxy or C 1 -C 8 -alkyl;
R 2 is C 1 -C 3 -alkyl;
R 5 is hydrogen or halogen;
R 3 is hydrogen, hydroxy, amino, —SO 2 R 8 , —SO 2 NH 2 , —SO 2 NR 9 R 10 , —NHSO 2 R 8 , cyano, carboxy, —OR 8 or C 1 -C 4 -haloalkyl;
R 8 is C 1 -C 8 -alkyl;
R 9 is C 1 -C 8 -alkyl optionally substituted by hydroxy, C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl;
R 10 is hydrogen or C 1 -C 8 -alkyl; or
R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl; and
R 12 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl.
6. A compound of formula I according to claim 1 , in free or salt form, wherein
R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by the group consisting of carboxy, C 1 -C 3 -alkoxy, C 1 -C 8 -alkoxycarbonyl, or nitrile;
R 2 is C 1 -C 3 -alkyl or halogen;
R 5 is hydrogen or halogen;
R 3 is hydrogen, hydroxy, amino, SOR 8 , SO 2 R 8 , SO 2 NH 2 , SO 2 NR 9 R 10 , COR 8 , CONHR 8 , NHSO 2 R 8 , nitrile, carboxy, OR 8 or C 1 -C 8 -haloalkyl;
R 4 is NR 12 R 13 ;
R 8 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by halogen, hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino;
R 9 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, amino, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl;
R 10 is hydrogen or C 1 -C 8 -alkyl; or
R 9 and R 10 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl; and
R 12 and R 13 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl.
7. A compound according to claim 6 wherein
R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by carboxy or C 1 -C 8 -alkoxycarbonyl;
R 2 is C 1 -C 3 -alkyl;
R 5 is hydrogen or halogen;
R 3 is hydrogen, hydroxy, amino, SO 2 R 8 , SO 2 NH 2 , SO 2 NR 9 R 10 , NHSO 2 R 8 , cyano, carboxy, OR 8 or C 1 -C 4 -haloalkyl;
R 4 is NR 12 R 13 ;
R 8 is C 1 -C 8 -alkyl;
R 9 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, optionally substituted by hydroxy, C 1 -C 8 -alkoxy, nitrile, di(C 1 -C 8 -alkyl)amino or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl;
R 10 is hydrogen or C 1 -C 8 -alkyl; or
R 9 and R 10 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 5 -alkyl; and
R 12 and R 13 together with the nitrogen atom to which they are attached form a 5 or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 -C 8 -alkyl.
8. A compound of claim 1 , that is also a compound of formula XIX
in free or salt form, wherein R a , R b , R c and R 1 are as shown in the following table:
R a
R b
R c
R 1
H
H
H
H
H
H
H
H
9. A compound of claim 1 , that is also a compound of formula XIX
in free or salt form, wherein R a , R b , R c and R 1 are as shown in the following table:
R a
R b
R c
R 1
H
H
10. A pharmaceutical composition comprising a compound according to claim 1 in combination with at least one drug substance which is an anti-inflammatory, a bronchodilator or an antihistamine drug substance.
11. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 , optionally together with a pharmaceutically acceptable diluent or carrier.
12. A pharmaceutical composition comprising as active ingredient a compound according to claim 8 , optionally together with a pharmaceutically acceptable diluent or carrier.
13. A pharmaceutical composition comprising as active ingredient a compound according to claim 9 , optionally together with a pharmaceutically acceptable diluent or carrier.
14. A compound of claim 1 , which compound has the formula:
in free or salt form.