2-aminoquinazoline derivatives as P70S6 kinase inhibitors

1. A compound of the formula (1):

or a salt, tautomer or N-oxide thereof;

wherein:

one of Y and Z is R 3 and the other is Ar 2 ;

Q 1 is a C 1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C 1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q 2 is attached; and wherein a carbon atom of the C 1-8 alkylene group may optionally be replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group provided that the total number of carbon atoms in an alkylene group containing such a replacement does not exceed 8;

Q 2 is a bond or a C 1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C 1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q 2 is attached;

R 1 is selected from hydrogen, NR x R y and a group Cy 1 ;

R x and R y are the same or different and each is selected from hydrogen, C 1-4 hydrocarbyl or hydroxy-C 1-4 hydrocarbyl; or NR x R y forms a 4 to 7-membered heterocyclic ring containing a total of 1 or 2 heteroatom ring members of which one is N and the other is selected from N, O and S and oxidised forms thereof, the heterocyclic ring being optionally substituted with one or two substituents selected from C 1-4 hydrocarbyl, oxo, amino, mono-C 1-4 hydrocarbylamino, di-C 1-4 hydrocarbylamino, fluorine and hydroxy, provided that there are at least two carbon atoms in line between the amino, mono-C 1-4 hydrocarbylamino, di-C 1-4 hydrocarbylamino and hydroxy substituents when present and the nitrogen atom of the NR x R y group;

Cy 1 is a C-linked 3 to 7 membered monocyclic non-aromatic carbocyclic or heterocyclic group containing 0, 1 or 2 heteroatom ring members selected from N, O and S and oxidised forms of S, and being optionally substituted with one or two substituents selected from C 1-3 hydrocarbyl, fluorine, oxo and hydroxy;

R 2 and R 4 are the same or different and each is selected from hydrogen, fluorine, chlorine, C 1-2 alkyl and C 1-2 alkoxy, wherein each C 1-2 alkyl and C 1-2 alkoxy is optionally substituted with two or more fluorine atoms;

R 3 is selected from hydrogen, fluorine, chlorine, C 1-2 alkyl and C 1-2 alkoxy, wherein each C 1-2 alkyl and C 1-2 alkoxy is optionally substituted with two or more fluorine atoms;

Ar 1 is a monocyclic 5 or 6-membered aryl or heteroaryl ring containing 0, 1 or 2 heteroatom ring members selected from O, N and S, the aryl or heteroaryl being optionally substituted with 1, 2 or 3 substituents R 5 which are the same or different and are selected from halogen, cyano and a group R a -R b ;

R a is a bond, O, CO, X 3 C(X 4 ), C(X 4 )X 3 , X 3 C(X 4 )X 3 , S, SO, SO 2 , NR c , SO 2 NR c or NR c SO 2 ;

R b is:

hydrogen;

a carbocyclic or heterocyclic group having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R 6 ; or

an acyclic C 1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C 1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R 6 ; wherein one or two but not all of the carbon atoms of the acyclic C 1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO 2 , NR c , X 3 C(X 4 ), C(X 4 )X 3 or X 3 C(X 4 )X 3 ;

R 6 is selected from the substituents R 5 except that R 6 does not consist of or contain a carbocyclic or heterocyclic group;

X 3 is O, S or NR c ; and

X 4 is ═O, ═S or ═NR c ; and

R c is hydrogen or C 1-4 hydrocarbyl;

Ar 2 is a bicyclic 8 to 11-membered heteroaryl group containing 1, 2, 3 or 4 heteroatom ring members selected from O, N and S and being optionally substituted with 1, 2 or 3 substituents R 7 selected from oxo, fluorine; chlorine; bromine; C 1-4 hydrocarbyl optionally substituted with one or more fluorine atoms; C 1-4 hydrocarbyloxy optionally substituted with one or more fluorine atoms; hydroxy; cyano; N(R c ) 2 ; R c —C(O)—; R c —C(O)N(R c )—; (R c ) 2 NC(O)—; R c —SO 2 NR c —; R c —NHC(O)NH—; (R c ) 2 NSO 2 —; and five and six-membered monocyclic groups containing from 0 to 3 heteroatom ring members selected from O, N and S, the five and six-membered monocyclic groups being unsubstituted or substituted with one or more substituents R 8 selected from C 1-4 hydrocarbyl, C 1-4 hydrocarbyloxy, cyano, hydroxy, oxo, halogen, amino, mono-C 1-4 hydrocarbylamino and di-C 1-4 hydrocarbylamino and wherein the hydrocarbyl moieties when present are optionally substituted with fluorine, C 1-2 alkoxy, hydroxy, amino, mono-di-C 1-2 alkylamino or di-C 1-4 alkylamino;

and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof.

2. A compound according to claim 1 having the formula (1):

or a salt, tautomer or N-oxide thereof;

wherein:

one of Y and Z is R 3 and the other is Are;

Q 1 is a C 1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C 1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q 2 is attached;

Q 2 is a bond or a C 1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C 1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q 2 is attached;

R 1 is selected from hydrogen, NR x R y and a group Cy 1 ;

R x and R y are the same or different and each is selected from hydrogen, C 1-4 hydrocarbyl or hydroxy-C 1-4 hydrocarbyl; or NR x R y forms a 4 to 7-membered heterocyclic ring containing a total of 1 or 2 heteroatom ring members of which one is N and the other is selected from N, O and S and oxidised forms thereof, the heterocyclic ring being optionally substituted with one or two substituents selected from C 1-4 hydrocarbyl, oxo, amino, mono-C 1-4 hydrocarbylamino, di-C 1-4 hydrocarbylamino, fluorine and hydroxy, provided that there are at least two carbon atoms in line between the amino, mono-C 1-4 hydrocarbylamino, di-C 1-4 hydrocarbylamino and hydroxy substituents when present and the nitrogen atom of the NR x R y group;

Cy 1 is a C-linked 3 to 7 membered monocyclic non-aromatic carbocyclic or heterocyclic group containing 0, 1 or 2 heteroatom ring members selected from N, O and S and oxidised forms of S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or two substituents selected from C 1-3 hydrocarbyl, fluorine, oxo and hydroxy;

R 2 and R 4 are the same or different and each is selected from hydrogen, fluorine, chlorine, C 1-2 alkyl and C 1-2 alkoxy, wherein each C 1-2 alkyl and C 1-2 alkoxy is optionally substituted with two or more fluorine atoms;

R 3 is selected from hydrogen, fluorine, chlorine, C 1-2 alkyl and C 1-2 alkoxy, wherein each C 1-2 alkyl and C 1-2 alkoxy is optionally substituted with two or more fluorine atoms;

Ar 1 is a monocyclic 5 or 6-membered aryl or heteroaryl ring containing 0, 1 or 2 heteroatom ring members selected from O, N and S, the aryl or heteroaryl being optionally substituted with 1, 2 or 3 substituents R 5 which are the same or different and are selected from halogen, cyano and a group R a -R b ;

R a is a bond, O, CO, X 3 C(X 4 ), C(X 4 )X 3 , X 3 C(X 4 )X 3 , S, SO, SO 2 , NR c , SO 2 NR c or NR c SO 2 ;

R b is:

hydrogen;

a carbocyclic or heterocyclic group having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R 6 ; or

an acyclic C 1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C 1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R 6 ; wherein one or two but not all of the carbon atoms of the acyclic C 1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO 2 , NR c , X 3 C(X 4 ), C(X 4 )X 3 or X 3 C(X 4 )X 3 ;

R 6 is selected from the substituents R 5 except that R 6 does not consist of or contain a carbocyclic or heterocyclic group;

X 3 is O, S or NR c ; and

X 4 is ═O, ═S or ═NR c ; and

R c is hydrogen or C 1-4 hydrocarbyl;

Ar 2 is a bicyclic 8 to 11-membered heteroaryl group containing 1, 2, 3 or 4 heteroatom ring members selected from O, N and S and being optionally substituted with 1, 2 or 3 substituents R 7 selected from oxo, fluorine; chlorine; bromine; C 1-4 hydrocarbyl optionally substituted with one or more fluorine atoms; C 1-4 hydrocarbyloxy optionally substituted with one or more fluorine atoms; hydroxy; cyano; N(R c ) 2 ; R c -C(O)-; R c -C(O)N(R c )-; (R c ) 2 NC(O)-; R c —SO 2 NR c -; R c -NHC(O)NH—; (R c ) 2 NSO 2 -; and five and six-membered monocyclic groups containing from 0 to 3 heteroatom ring members selected from O, N and S, the five and six-membered monocyclic groups being unsubstituted or substituted with one or more substituents R 8 selected from C 1-4 hydrocarbyl, C 1-4 hydrocarbyloxy, cyano, hydroxy, oxo, halogen, amino, mono-C 1-4 hydrocarbylamino and di-C 1-4 hydrocarbylamino and wherein the hydrocarbyl moieties when present are optionally substituted with fluorine, C 1-2 alkoxy, hydroxy, amino, mono-di-C 1-2 alkylamino or di-C 1-4 alkylamino;

and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof.

3. A compound according to claim 1 wherein Y is Are and Z is R 3 .

4. A compound according to claim 1 wherein Q 1 is C 1-4 alkylene optionally substituted by one or two substituents selected from hydroxy and C 1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q 2 is attached.

5. A compound according to claim 4 wherein Q 1 is selected from CH 2 , CH(CH 3 ), CH(CH 2 OH) and CH(CH 2 CH 2 OH).

6. A compound according to claim 1 wherein Q 2 is a bond or C 1-3 alkylene.

7. A compound according to claim 1 wherein R 1 is selected from:

hydrogen;

a group Cy 1 wherein Cy 1 is selected from 4 to 7 membered saturated heterocyclic groups containing a first ring member which is nitrogen and optionally a second ring member selected from N, O and S, wherein the heterocyclic groups are optionally substituted with one or two substituents selected from C 1-3 alkyl, cyclopropyl, fluorine and hydroxyl; and

NR x R y , wherein R x and R y are the same or different and each is selected from hydrogen, C 1-4 alkyl, cyclopropyl, methylcyclopropyl, cyclopropylmethyl, and hydroxy-C 2-4 alkyl.

8. A compound according to claim 7 wherein R 1 is hydrogen.

9. A compound according to claim 1 wherein Ar 1 is a monocyclic aryl or heteroaryl ring selected from phenyl, furyl, thienyl and pyridyl, each optionally substituted with 1, 2 or 3 substituents R 5 which are the same or different.

10. A compound according to claim 9 wherein Ar 1 is a phenyl ring optionally substituted with 1, 2 or 3 substituents R 5 which are the same or different.

11. A compound according to claim 1 wherein R 2 is hydrogen.

12. A compound according to claim 1 wherein R 3 is hydrogen.

13. A compound according to claim 1 wherein R 4 is hydrogen.

14. A compound according to claim 1 wherein the compound is of the formula (3):

or a salt, tautomer or N-oxide thereof, wherein R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 and Ar 1 are as defined in claim 1 .

15. A compound according to claim 1 wherein the compound is of the formula (4):

or a salt, tautomer or N-oxide thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , Q 1 and Q 2 are as defined in claim 1 and x is 0, 1, 2, or 3.

16. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable excipient.

17. A compound according to claim 1 which is selected from the group consisting of:

((R)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

((R)-1-(3-Chloro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

((R)-1-(3-Fluoro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

((R)-1-(4-Fluoro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

((S)-2-Hydroxy-1-phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

Benzyl-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-methylamine;

(3-Fluorobenzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

((R)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-b]pyridin-4-yl)-quinazolin-2-yl]-amine;

Benzyl-(S)-1-morpholin-3-ylmethyl-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

[(R)-1-(3,4-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

Benzyl-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

(3,4-Difluoro-benzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

N-(3-{[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-methyl}-phenyl)-methanesulfonamide;

[(R)-1-(3-Methoxy-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

[(R)-1-(2-Fluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

N-(3-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenyl)-methanesulfonamide;

(R)-3-Phenyl-3-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-propan-1-ol

[(R)-1-(2,4-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

[(R)-1-(2,6-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

2-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol;

3-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol;

4-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol;

(S)-2-(2-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol;

(S)-2-(3-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol; and

(S)-2-(4-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol;

and pharmaceutically acceptable salts thereof.

18. A compound according to claim 1 which is selected from the group consisting of:

((R)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

((R)-1-(3-Chloro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

((R)-1-(3-Fluoro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

((R)-1-(4-Fluoro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

(3-Fluorobenzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

[(R)-1-(3,4-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

[(R)-1-(2-Fluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

(R)-3-Phenyl-3-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-propan-1-ol;

[(R)-1-(2,4-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

[(R)-1-(2,6-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

2-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol;

3-{(R)-1-[6-(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethyl}-phenol; and

(S)-2-(2-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol;

and pharmaceutically acceptable salts thereof.

19. A compound according to claim 1 which is selected from the group consisting of:

((R)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

((R)-1-(3-Fluoro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

((R)-1-(4-Fluoro-phenyl)-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

(3-Fluorobenzyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

[(R)-1-(3,4-Difluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine;

[(R)-1-(2-Fluoro-phenyl)-ethyl]-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine; and

(S)-2-(2-Fluoro-phenyl)-2-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-ylamino]-ethanol;

and pharmaceutically acceptable salts thereof.

20. ((R)-1-Phenyl-ethyl)-[6-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-quinazolin-2-yl]-amine or a pharmaceutically acceptable salt thereof.