5-Phenylthiazole derivatives and their use as p13 kinase inhibitors

1. A compound of formula I

in free or salt form, wherein

R 1 is a 5 or 6-membered heterocyclic ring containing nitrogen and optionally one or more further hetero atoms selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by halo, C 1 -C 8 -alkyl optionally substituted by —NR 6 R 7 , carboxy, C 1 -C 8 -alkoxycarbonyl or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkoxy, —NR 6 R 7 , C 3 -C 8 -cycloalkyl optionally substituted by carboxy, or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen and oxygen, that ring being optionally substituted by C 1 -C 8 -alkyl;

R 2 is C 1 -C 8 -alkyl or halo;

R 3 is —SO 2 NR 8 R 9 , —SOR 10 or —SO 2 R 11 and is in the para or meta position with respect to the indicated thiazole ring;

R 4 and R 5 are each independently hydrogen, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy optionally substituted by a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by halo, halo-C 1 -C 8 -alkyl, cyano, —SO 2 NH 2 , carboxy, amino, amino-C 1 -C 8 -alkyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkoxy, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkoxy, aminocarbonyl, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, —NR 12 R 13 , carboxy-C 1 -C 8 -alkyl, carboxy-C 1 -C 8 -alkoxy, R 14 , —OR 14 or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl;

R 6 is hydrogen or C 1 -C 8 -alkyl;

R 7 is C 1 -C 8 -alkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy, di(C 1 -C 8 -alkyl)amino or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl;

R 8 is hydrogen or C 1 -C 8 -alkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy, cyano, 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 9 is hydrogen, C 1 -C 8 -alkyl optionally substituted by hydroxy, or C 3 -C 8 -cycloalkyl;

R 10 is C 1 -C 8 -alkyl;

R 11 is C 1 -C 8 -alkyl optionally substituted by halogen, hydroxy, C 1 -C 8 -alkoxy, cyano, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino;

R 12 is hydrogen or C 1 -C 8 -alkyl;

R 13 is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl optionally substituted by hydroxy, amino, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino or R 12 and R 13 together with the nitrogen atom to which they are attached form a 5 or 6-membered saturated or unsaturated 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 14 is C 1 -C 8 -alkyl optionally substituted by hydroxy or —NR 12 R 13 .

2. A compound according to claim 1 , in free or salt form, wherein

R 1 is a 5 or 6-membered heterocyclic ring containing nitrogen and optionally one or more further hetero atoms selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by halo, C 1 -C 8 -alkyl optionally substituted by —NR 6 R 7 , carboxy, C 1 -C 8 -alkoxycarbonyl or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, C 1 -C 8 -alkoxy, —NR 6 R 7 , C 3 -C 8 -cycloalkyl optionally substituted by carboxy, or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen and oxygen, that ring being optionally substituted by C 1 -C 8 -alkyl;

R 2 is C 1 -C 8 -alkyl;

R 3 is —SO 2 NR 8 R 9 , —SOR 10 , or —SO 2 R 11 and is in the para or meta position with respect to the indicated thiazole ring;

R 4 is hydrogen, C 1 -C 8 -alkoxy optionally substituted by a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by halo, halo-C 1 -C 8 -alkyl, —SO 2 NH 2 , —NR 12 R 13 or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl;

R 5 is hydrogen;

R 6 is hydrogen or C 1 -C 8 -alkyl;

R 7 is C 1 -C 8 -alkyl optionally substituted by hydroxy, di(C 1 -C 8 -alkyl)amino or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen and oxygen, that ring being optionally substituted by C 1 -C 8 -alkyl;

R 8 is hydrogen or C 1 -C 8 -alkyl optionally substituted by di(C 1 -C 8 -alkyl)amino;

R 9 is hydrogen, C 1 -C 8 -alkyl optionally substituted by hydroxy, or C 3 -C 8 -cycloalkyl;

R 10 is C 1 -C 8 -alkyl;

R 11 is C 1 -C 8 -alkyl;

R 12 is C 1 -C 8 -alkyl; and

R 13 is C 1 -C 8 -alkyl optionally substituted by di(C 1 -C 8 -alkyl)amino.

3. A compound according to claim 2 , in free or salt form, wherein

R 1 is a 5 or 6-membered heterocyclic ring containing nitrogen and optionally one or more further hetero atoms selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by halo, C 1 -C 4 -alkyl optionally substituted by —NR 6 R 7 , carboxy, C 1 -C 4 -alkoxycarbonyl or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, C 1 -C 4 -alkoxy, —NR 6 R 7 , C 3 -C 6 -cycloalkyl optionally substituted by carboxy, or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen and oxygen, that ring being optionally substituted by C 1 -C 4 -alkyl;

R 2 is C 1 -C 4 -alkyl;

R 3 is —SO 2 NR 8 R 9 , —SOR 10 , —SO 2 R 11 and is in the para or meta position with respect to the indicated thiazole ring;

R 4 is hydrogen, C 1 -C 4 -alkoxy optionally substituted by a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by halo, halo-C 1 -C 4 -alkyl, —SO 2 NH 2 , —NR 12 R 13 or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, that ring being optionally substituted by C 1 -C 4 -alkyl;

R 5 is hydrogen;

R 6 is hydrogen or C 1 -C 4 -alkyl;

R 7 is C 1 -C 4 -alkyl optionally substituted by hydroxy, di(C 1 -C 4 -alkyl)amino or a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen and oxygen, that ring being optionally substituted by C 1 -C 4 -alkyl;

R 8 is hydrogen or C 1 -C 4 -alkyl optionally substituted by di(C 1 -C 4 -alkyl)amino;

R 9 is hydrogen, C 1 -C 4 -alkyl optionally substituted by hydroxy, or C 3 -C 5 -cycloalkyl;

R 10 is C 1 -C 4 -alkyl;

R 11 is C 1 -C 4 -alkyl;

R 12 is C 1 -C 4 -alkyl; and

R 13 is C 1 -C 4 -alkyl optionally substituted by di(C 1 -C 4 -alkyl)amino.

4. A compound according to claim 1 , which is also a compound of formula XII

wherein R a , R b and R 1 are as shown in the following table:

R a

R b

R 1

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

—SO 2 NH 2

H

H

H

H

H

—OCH 3

—SO 2 NH 2

—SO 2 NH 2

Cl

—SO 2 NH 2

Cl

—SO 2 NH 2

H

—SO 2 NH 2

H

H

H

H

Cl

H

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

—CF 3

—CF 3

—CF 3

—CF 3

—CF 3

—CF 3

—CF 3

—CF 3

—CF 3

F

F

F

5. A pharmaceutical composition comprising a compound according to claim 1 , optionally together with a pharmaceutically acceptable diluent or carrier.

6. A pharmaceutical composition according to claim 5 further comprising one or more anti-inflammatory, bronchodilatory or antihistamine drug substances, wherein the anti-inflammatory drug substance is selected from the group consisting of steroids, LTB4 antagonists, LTD4 antagonists, dopamine receptor agonists and PDE4 inhibitors; the bronchodilatory drug substance is selected from the group consisting of anticholinergic agents, antimuscarinic agents and beta-2 adrenoceptor agonists; and the antihistamine drug substance is selected from the list consisting of cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, and fexofenadine hydrochloride.

7. A pharmaceutical composition comprising a compound according to claim 4 , optionally together with a pharmaceutically acceptable diluent or carrier.

8. A process for the preparation of a compound of formula I as defined in claim 1 that

comprises the steps of:

(i) (A) reacting a compound of formula II

wherein R 2 , R 3 , R 4 and R 5 are as hereinbefore defined in claim 1 and X is halogen, with a compound of formula III

wherein R 1 is as hereinbefore defined in claim 1 ;

(B) reacting a compound of formula IV

wherein R 2 , R 3 , R 4 and R 5 are as hereinbefore defined in claim 1 and X is halogen, with a compound of formula R 1 —NH 2 , optionally in the presence of a base;

(C) for the preparation of compounds of formula I where R 1 is a 5 or 6-membered heterocyclic ring containing nitrogen and optionally a further hetero atom of the group consisting of nitrogen, oxygen and sulphur that is substituted by —NR 6 R 7 , reacting a compound of formula I where R 1 is a 5 or 6-membered heterocyclic ring containing nitrogen and optionally a further hetero atom of the group consisting of nitrogen, oxygen and sulphur that is substituted by halo with a compound of formula V

wherein R 6 and R 7 are as hereinbefore defined in claim 1 , optionally in the presence of a base;

(D) for the preparation of compounds of formula I where R 3 is —SO 2 NR 8 R 9 , reacting a compound of formula VI

wherein R 2 , R 4 , R 5 and X are as hereinbefore defined in claim 1 with an amine of formula VII

wherein R 8 and R 9 are as hereinbefore defined in claim 1 ; or

(E) for the preparation of compounds of formula I where one or both of R 4 and R 5 is —NR 12 R 13 , reacting a compound of formula I wherein R 1 and R 2 are hereinbefore defined, R 3 is —SO 2 R 11 or —SO 2 NH 2 and one or both of R 4 and R 5 is halo with a compound of formula VIII

wherein R 12 and R 13 are hereinbefore defined, optionally in the presence of a base; or

(F) for the preparation of compounds of formula I where one or both of R 4 and R 5 is C 1 -C 8 -alkoxy substituted by a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, reacting a compound of formula I wherein R 1 and R 2 are hereinbefore defined, R 3 is —SO 2 R 11 or —SO 2 NH 2 and one or both of R 4 and R 5 is halo with a compound of formula HO—C 1 -C 8 -alkyl-W where W is a 5 or 6-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulphur, optionally in the presence of a base; and

(ii) recovering the resultant compound of formula I in free or salt form.