Substituted isoquinolinones and quinazolinones

1. A compound of formula (I), or pharmaceutically acceptable salt thereof,

wherein

Z is CH 2 ;

X is halogen;

R 6 is independently selected from the group consisting of

H—

R′O—

(R′) 2 N—;

R 7 is independently selected from the group consisting of

R′O—

(R′) 2 N—;

each R′ is independently selected from the group consisting of

H—

C 1 -C 7 -alkyl-

C 1 -C 7 -alkenyl-

halo-C 1 -C 7 -alkyl-

halo-C 1 -C 7 -alkenyl-

C 3 -C 12 -cycloalkyl-

heterocyclyl-

aryl-

hydroxy-C 1 -C 7 -alkyl-

C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-

amino-C 1 -C 7 -alkyl-

N—C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-

N,N-di-C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-

C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl- heterocyclyl-C 1 -C 7 -alkyl-

aryl-C 1 -C 7 -alkyl-

C 1 -C 7 -alkyl-carbonyl-

halo-C 1 -C 7 -alkyl-carbonyl-

hydroxy-C 1 -C 7 -alkyl-carbonyl-

C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-carbonyl-

amino-C 1 -C 7 -alkyl-carbonyl-

N—C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-carbonyl-

N,N-di-C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-carbonyl-

C 3 -C 12 -cycloalkyl-carbonyl-

heterocyclyl-C 1 -C 7 -alkyl-carbonyl-

aryl-C 1 -C 7 -alkyl-carbonyl-

C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl-carbonyl-

heterocyclyl-carbonyl-

aryl-carbonyl-

C 1 -C 7 -alkyl-carbonyl-C 1 -C 7 -alkyl-

halo-C 1 -C 7 -alkyl-carbonyl-C 1 -C 7 -alkyl-

hydroxy-C 1 -C 7 -alkyl-carbonyl-C 1 -C 7 -alkyl-

C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-carbonyl-C 1 -C 7 -alkyl-

amino-C 1 -C 7 -alkyl-carbonyl-C 1 -C 7 -alkyl-

N—C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-carbonyl-C 1 -C 7 -alkyl-

N,N-di-C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-carbonyl-C 1 -C 7 -alkyl-

C 3 -C 12 -cycloalkyl-carbonyl-C 1 -C 7 -alkyl-

heterocyclyl-carbonyl-C 1 -C 7 -alkyl-

aryl-carbonyl-C 1 -C 7 -alkyl-

carbonyl-C 1 -C 7 -alkyl-

hydroxy-carbonyl-C 1 -C 7 -alkyl-

C 1 -C 7 -alkoxy-carbonyl-C 1 -C 7 -alkyl-

amino-carbonyl-C 1 -C 7 -alkyl-

N—C 1 -C 7 -alkyl-amino-carbonyl-C 1 -C 7 -alkyl-

N,N-di-C 1 -C 7 -alkyl-amino-carbonyl-C 1 -C 7 -alkyl-

C 3 -C 12 -cycloalkyl-carbonyl-C 1 -C 7 -alkyl-

heterocyclyl-carbonyl-C 1 -C 7 -alkyl-

aryl-carbonyl-C 1 -C 7 -alkyl-

C 1 -C 7 -alkyl-carbonyl-amino-C 1 -C 7 -alkyl-

C 1 -C 7 -alkyl-carbonyl-N—C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-

halo-C 1 -C 7 -alkyl-carbonyl-amino-C 1 -C 7 -alkyl-

halo-C 1 -C 7 -alkyl-carbonyl-N—C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-

wherein aryl, heterocyclyl and C 3 -C 12 -cycloalkyl are unsubstituted or substituted by 1-4 substituents selected from C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, halogen, hydroxy, C 1 -C 7 -alkoxy, amino, nitro or cyano;

each R 1 is independently selected from the group consisting of

halogen-

cyano-

nitro-

C 1 -C 7 -alkyl-

C 1 -C 7 -alkenyl-

halo-C 1 -C 7 -alkyl-

hydroxy-

C 1 -C 7 -alkoxy-

amino-

N—C 1 -C 7 -alkyl-amino-

N,N-di-C 1 -C 7 -alkyl-amino-

amino-carbonyl-amino-

N—C 1 -C 7 -alkyl-amino-carbonyl-amino-

N,N-di-C 1 -C 7 -alkyl-amino-carbonyl-amino-

C 1 -C 7 -alkyl-carbonyl-amino-

amino-carbonyl-

N—C 1 -C 7 -alkyl-amino-carbonyl-

N,N-di-C 1 -C 7 -alkyl-amino-carbonyl-

hydroxy-C 1 -C 7 -alkyl-

amino-C 1 -C 7 -alkyl-

N—C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-

N,N-di-C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-

C 1 -C 7 -alkyl-carbonyl-amino-C 1 -C 7 -alkyl-

C 1 -C 7 -alkyl-carbonyl-N—C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-;

n is 0 to 2;

R 2 is selected from

(A) phenyl, 2-pyridyl and 3-pyridyl substituted in the para-position relative to the isoquinolinone or quinazolinone, by (R 3 ) 2 N—Y—

wherein Y is absent (a bond) or

(R 3 ) 2 N—Y— is selected from

and wherein said phenyl, 2-pyridyl or 3-pyridyl is optionally substituted by 1-2 additional substituents selected from

halogen-

cyano-

C 1 -C 7 -alkyl-

halo-C 1 -C 7 -alkyl-

hydroxy-

C 1 -C 7 -alkoxy- and

hydroxy-C 1 -C 7 -alkyl-;

or

(B) phenyl, 2-pyridyl or 3-pyridyl

substituted in para-position relative to the isoquinolinone or quinazolinone by a substituent selected from

cyano-

halogen-

nitro-

C 1 -C 7 -alkyl-

halo-C 1 -C 7 -alkyl-

hydroxy-C 1 -C 7 -alkyl-

hydroxy-carbonyl-

C 1 -C 7 -alkoxy-carbonyl-

C 1 -C 7 -alkyl-carbonyl-

C 1 -C 7 -alkoxy-

(C-bound)-heterocyclyl-

wherein (C-bound)-heterocyclyl is unsubstituted or substituted by 1-4 substituents selected from C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, halogen, hydroxy, C 1 -C 7 -alkoxy, amino, nitro or cyano;

and optionally substituted by 1-2 additional substituents selected from

halogen-

cyano-

C 1 -C 7 -alkyl-

halo-C 1 -C 7 -alkyl-

hydroxy-

C 1 -C 7 -alkoxy-

(C-bound or N-bound)heterocyclyl-C 1 -C 4 -alkyl-

hydroxy-C 1 -C 7 -alkyl-;

or

(C) phenyl,

substituted in ortho-position relative to the isoquinolinone or quinazolinone by

R 3 O— and

substituted in para- or meta-position by a substituent selected from methyl, chloro, C 1 -C 7 -alkyl-carbonyl- or C 1 -C 7 -alkoxy-carbonyl-;

(D) (C-bound)-heterocycle selected from

wherein Z is a 4-6 membered heterocyclic ring, annulated to phenyl in para and meta position, containing 1-3 heteroatoms selected from N, O or S,

which is optionally substituted by 1-2 additional substituents selected from

halogen-

cyano-

C 1 -C 7 -alkyl-

halo-C 1 -C 7 -alkyl-

hydroxy-

C 1 -C 7 -alkoxy-

hydroxy-C 1 -C 7 -alkyl-;

(E) pyrazin-2-yl,

substituted at the 5 position by:

(F) pyridazin-3-yl, substituted at the 6 position by:

(G) pyrimidin-2-yl, substituted at the 5 position by:

wherein each R 3 is independently selected from

H—

C 1 -C 7 -alkyl-

hydroxy-C 1 -C 7 -alkyl-

C 3 -C 12 -cycloalkyl-

C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl-carbonyl-

amino-C 1 -C 7 -alkyl-carbonyl

N—C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-carbonyl

N,N-di C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-carbonyl

(R 5 ) 2 N—C 3 -C 12 -cycloalkyl-

(R 5 ) 2 N—C 1 -C 7 -alkyl-

(R 5 ) 2 N—C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl-

(R 5 ) 2 N—C 3 -C 12 -cycloalkyl-carbonyl-

R 5 O—C 3 -C 12 -cycloalkyl-

R 5 O—C 1 -C 7 -alkyl-

R 5 O—C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl-

R 5 O—(C 1 -C 7 -alkyl)-C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl-

R 5 O—(hydroxy-C 1 -C 7 -alkyl)-C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl-

(R 5 ) 2 N—CO—C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl-

C 1 -C 7 -alkoxycarbonyl-C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl-

hydroxycarbonyl-C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl-

amino-carbonyl-C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl-

R 5 O—C 3 -C 12 -cycloalkyl-carbonyl-

(R 5 ) 2 N-carbonyl-C 1 -C 7 -alkyl-

R 5 O-carbonyl-C 1 -C 7 -alkyl-

aryl-C 1 -C 7 -alkyl-

heterocyclyl-C 1 -C 7 -alkyl-

C 1 -C 7 -alkyl-carbonyl-

halo-C 1 -C 7 -alkyl-carbonyl-

heterocyclyl-carbonyl-

aryl-carbonyl-

C 3 -C 12 -cycloalkyl-carbonyl-

C 3 -C 12 -cycloalkyl-C 1 -C 7 -alkyl-

heterocyclyl-

aryl-

wherein aryl, heterocyclyl and C 3 -C 12 -cycloalkyl are unsubstituted or substituted by 1-4 substituents selected from halogen-

C 1 -C 7 -alkyl-

halo-C 1 -C 7 -alkyl-

C 1 -C 7 -alkyl-carbonyl-

C 3 -C 12 -cycloalkyl-carbonyl-

C 1 -C 7 -alkyl-sulfonyl-

amino-sulfonyl-

N—C 1 -C 7 -alkyl-amino-sulfonyl-

N,N-di-C 1 -C 7 -alkyl-amino-sulfonyl-

amino-carbonyl-

N—C 1 -C 7 -alkyl-amino-carbonyl-

N,N-di-C 1 -C 7 -alkyl-amino-carbonyl-

oxo=

or

two R 3 , together with the N to which they are attached my form a 3-9 membered heterocyclic ring, optionally containing 1-4 additional heteroatoms selected from N, O or S, said heterocyclic ring is unsubstituted or substituted by 1-3 substituents selected from:

halogen-

hydroxy-C 1 -C 7 -alkyl-

C 1 -C 7 -alkyl-

halo-C 1 -C 7 -alkyl-

oxo=

hydroxy-

C 1 -C 7 -alkoxy-

amino-

N—C 1 -C 7 -alkyl-amino-

N,N-di-C 1 -C 7 -alkyl-amino-

hydroxy-carbonyl-

C 1 -C 7 -alkoxy-carbonyl-

amino-carbonyl-

N—C 1 -C 7 -alkyl-amino-carbonyl-

N,N-di-C 1 -C 7 -alkyl-amino-carbonyl-

C 1 -C 7 -alkyl-carbonyl-

C 1 -C 7 -alkyl-sulphonyl-

heterocyclyl-

C 1 -C 7 -alkyl-carbonyl-amino-

C 1 -C 7 -alkyl-carbonyl-N—C 1 -C 7 -alkyl-amino-; and

each R 5 is independently selected from:

H—

C 1 -C 7 -alkyl-

hydroxy-C 1 -C 7 -alkyl-

C 1 -C 7 -alkyl-carbonyl-

C 1 -C 7 -alkoxy-carbonyl-C 1 -C 7 -alkyl-

amino-carbonyl-C 1 -C 7 -alkyl-

N—C 1 -C 7 -alkyl-amino-carbonyl-C 1 -C 7 -alkyl-

N,N-di-C 1 -C 7 -alkyl-amino-carbonyl-C 1 -C 7 -alkyl-

C 1 -C 7 -alkyl-sulfonyl-

amino-sulfonyl-

N—C 1 -C 7 -alkyl-amino-sulfonyl-

N,N-di-C 1 -C 7 -alkyl-amino-sulfonyl-

heterocyclyl-carbonyl-

amino-carbonyl-

N—C 1 -C 7 -alkyl-amino-carbonyl-

N,N-di-C 1 -C 7 -alkyl-amino-carbonyl-

C 3 -C 12 -cycloalkyl-carbonyl-

C 1 -C 7 -alkoxy-carbonyl-amino-C 1 -C 7 -alkyl-

C 1 -C 7 -alkoxy-carbonyl-N—C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl-

C 1 -C 7 -alkoxy-carbonyl-

C 3 -C 12 -cycloalkyl-

hydroxy-C 3 -C 12 -cycloalkyl-

or

two R 5 , together with the N to which they are attached my form a 3-9 membered heterocyclic ring, optionally containing from 1-4 additional heteroatoms selected from N, O or S, said heterocyclic ring is unsubstituted or substituted by from 1 to 3 substituents selected from

C 1 -C 7 -alkyl-

oxo=,

C 1 -C 7 -alkyl-carbonyl,

C 1 -C 7 -alkyl-sulphonyl,

hydroxy-C 1 -C 7 -alkyl;

with the proviso that if Z is CH 2 , n is 0 or 1, and when present, R 1 is ortho-chloro, and R 2 is selected from

para-C 1 -C 3 -alkyl-phenyl-

para-(halo-C 1 -C 3 -alkyl)-phenyl-

para-C 1 -C 3 -alkoxy-phenyl-

para-halo-phenyl-

para-nitro-phenyl-

para-(C 1 -C 3 -alkoxy-carbonyl)-phenyl-

para-(hydroxy-carbonyl)-phenyl-

wherein the phenyl is optionally substituted by 1-2 additional substituents, said substituents being independently selected from halo and methyl,

then R 6 and R 7 are not both ethoxy or methoxy,

aryl means phenyl or naphthyl,

and

heterocyclyl means an unsaturated, saturated, or partially saturated ring or ring system comprising 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, and containing at least one heteroatom selected from N, O and S, where the N and S can also optionally be oxidized, and wherein, unless otherwise stated, the heterocyclic group can be attached at a heteroatom or a carbon atom.

2. A compound of formula (I), or pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein X is chloro.

3. A compound of formula (I), or pharmaceutically acceptable salt thereof, according to claim 1 , wherein each R′ is independently selected from

H—

C 1 -C 6 -alkyl-

heterocyclyl-C 1 -C 4 -alkyl-

amino-C 1 -C 4 -alkyl-

N—C 1 -C 4 -alkyl-amino-C 1 -C 4 -alkyl-

N,N-di-C 1 -C 4 -alkyl-amino-C 1 -C 4 -alkyl-

heterocyclyl-carbonyl-C 1 -C 4 -alkyl-

hydroxy-C 1 -C 4 -alkyl-

amino-carbonyl-C 1 -C 4 -alkyl-

N—C 1 -C 4 -alkyl-amino-carbonyl-C 1 -C 4 -alkyl-

N,N-di-C 1 -C 4 -alkyl-amino-carbonyl-C 1 -C 4 -alkyl-

d 3 methoxy,

C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl-

C 3 -C 7 -cycloalkyl-

aryl-C 1 -C 4 -alkyl-

C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-

C 1 -C 6 -alkenyl-

halo-C 1 -C 4 -alkyl-

halo-C 1 -C 4 -alkenyl-

C 1 -C 4 -alkyl-carbonyl-

C 1 -C 4 -alkyl-carbonyl-amino-C 1 -C 4 -alkyl-

aryl-C 1 -C 4 -alkyl-

heterocyclyl- and

aryl-

wherein said C 3 -C 7 -cycloalkyl (including the C 3 -C 7 -cycloalkyl substituent within C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl-), is optionally substituted by hydroxy or methyl, and wherein aryl (including within aryl-C 1 -C 4 -alkyl-), and heterocyclyl (including within heterocyclyl-C 1 -C 4 -alkyl- and heterocyclyl-carbonyl-C 1 -C 4 -alkyl-), is optionally substituted by 1 or 2 C 1 -C 4 -alkyl substituents.

4. A compound of formula (I), or pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 6 is R′O—.

5. A compound of formula (I), or pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 2 is R′O—.

6. A compound of formula (I), or pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 2 is selected from:

(A) phenyl, 2-pyridyl or 3-pyridyl substituted in para-position relative to the isoquinolinone or quinazolinone by

(R 3 ) 2 N—Y—

wherein Y is absent (a bond) or

(R 3 ) 2 N—Y— is selected from

and wherein said phenyl, 2-pyridyl or 3-pyridyl are optionally substituted by 1-2 additional substituents selected from

halogen-

cyano-

C 1 -C 4 -alkyl-

halo-C 1 -C 4 -alkyl-

hydroxy-

C 1 -C 4 -alkoxy-

hydroxy-C 1 -C 4 -alkyl-.

7. A compound of formula (I), or pharmaceutically acceptable salt thereof, as claimed in claim 6 , wherein R 2 is selected from:

(A) phenyl, 2-pyridyl or 3-pyridyl, substituted in para-position relative to the isoquinolinone or quinazolinone by (R 3 ) 2 N—Y—, wherein Y is absent (a bond), and

wherein the phenyl, 2-pyridyl or 3-pyridyl are not further substituted.

8. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein each R 3 is independently selected from:

C 1 -C 4 -alkyl-

C 3 -C 2 -cycloalkyl-C 1 -C 4 -alkyl-

heterocyclyl-C 1 -C 4 -alkyl-

aryl-C 1 -C 4 -alkyl-

(R 5 ) 2 N—C 3 -C 2 -cycloalkyl-

(R 5 ) 2 N—C 3 -C 2 -cycloalkyl-C 1 -C 4 -alkyl-

(R 5 ) 2 N—CO—C 3 -C 2 -cycloalkyl-C 1 -C 4 -alkyl-

aryl-

heterocyclyl-

C 3 -C 2 -cycloalkyl-

wherein aryl, heterocyclyl and C 3 -C 7 -cycloalkyl are unsubstituted or substituted by 1-4 substituents selected from

halogen-

C 1 -C 4 -alkyl-

halo-C 1 -C 4 -alkyl-

C 1 -C 4 -alkyl-carbonyl-

C 3 -C 2 -cycloalkyl-carbonyl-

C 1 -C 4 -alkyl-sulfonyl-

amino-sulfonyl-

N—C 1 -C 4 -alkyl-amino-sulfonyl-

N,N-di-C 1 -C 4 -alkyl-amino-sulfonyl-

amino-carbonyl-

N—C 1 -C 4 -alkyl-amino-carbonyl-

N,N-di-C 1 -C 4 -alkyl-amino-carbonyl- and

oxo=.

9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 2 is selected from (A) phenyl, 2-pyridyl or 3-pyridyl, substituted in para-position by (R 3 ) 2 N—Y—, wherein Y is absent, and wherein one R 3 is C 1 -C 4 -alkyl-, and the other R 3 is (R 5 ) 2 N-cyclohexyl-C 1 -C 2 -alkyl-, and wherein the two R 5 , together with the N to which they are attached form a 6 membered heterocyclic ring, optionally containing 1 additional N heteroatom and/or optionally containing an O atom and/or a S atom, said heterocyclic ring being unsubstituted or substituted by 1 or 2 substituents independently selected from

C 1 -C 4 -alkyl-,

oxo=,

C 1 -C 4 -alkyl-carbonyl,

C 1 -C 4 -alkyl-sulphonyl, and

hydroxy-C 1 -C 4 -alkyl.

10. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein when two R 3 substituents are present, and they do not join to form a ring, at least one R 3 substituent is C 1 -C 4 -alkyl-.

11. A compound of the formula (I) as claimed in claim 1 , in combination with one or more therapeutically active agents.

12. A compound that is (S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one or a pharmaceutically acceptable salt thereof.

13. A compound, or a pharmaceutically acceptable salt thereof, selected from:

14. A crystalline form I of (S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino]-phenyl)-1,4-dihydro-2H-isoquinolin-3-one sulphate salt having a powder X ray diffraction pattern using Cu Kα radiation which includes the following peaks: Angle 2-Theta °: 18.8, 21.3 and 22.7, error +/−0.2°.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined in claim 1 , and one or more pharmaceutically acceptable carriers.