Compounds and methods for treating cancer and inflammation

1 . A pharmaceutical composition useful in treating cancer, inflammation or a hyperproliferative disorder in a human, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (I):

wherein:

a is 0 to 4;

R 1 is carbocyclyl or heterocyclyl;

each R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, halo, haloalkyl, haloalkenyl, nitro, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, —OR 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —R 9 —N═N—O—R 8 , —S(O) p R 7 (where p is 0 to 2), and —S(O) p N(R 7 ) 2 (where p is 0 to 2);

R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, halo, haloalkyl, haloalkenyl, nitro, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, —OR 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —R 9 —N═N—O—R 8 , —S(O) p R 7 (where p is 0 to 2), and —S(O) p N(R 7 ) 2 (where p is 0 to 2);

R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkenyl and heterocyclylalkyl;

each R 7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl;

each R 8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl; and

R 9 is a bond or a straight or branched alkylene or alkenylene chain;

as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a solvate or polymorph; or as a pharmaceutically acceptable salt thereof,

with the proviso that R 1 can not be unsubstituted phenyl when all of the following occur:

(i) a is 2 and one R 2 is methoxy in the 6-position of the isoquinolone ring and the other R 2 is methoxy in the 7-position of the isoquinolone ring; and

(ii) R 3 , R 5 and R 6 are all hydrogen, and

(iii) R 4 is 3,4-dimethoxybenzyl.

2 .- 39 . (canceled)

40 . A method of treating cancer, inflammation or a hyperproliferative disorder in a mammal, which method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I):

wherein:

a is 0 to 4;

R 1 is carbocyclyl or heterocyclyl;

each R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, halo, haloalkyl, haloalkenyl, nitro, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, —OR 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —N(R 7 ) 2 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)R 7 , —R 9 —N═N—O—R 8 , —S(O) p R 7 (where p is 0 to 2), and —S(O) p N(R 7 ) 2 (where p is 0 to 2);

R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, halo, haloalkyl, haloalkenyl, nitro, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, —OR 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —N(R 7 ) 2 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)R 7 , —R 9 —N═N—O—R 8 , —S(O) p R 7 (where p is 0 to 2), and —S(O) p N(R 7 ) 2 (where p is 0 to 2);

R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkenyl and heterocyclylalkyl; each R 7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl;

each R 8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl; and

R 9 is a bond or a straight or branched alkylene or alkenylene chain;

as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a solvate or polymorph; or as a pharmaceutically acceptable salt thereof.

41 . (canceled)

42 . The method according to claim 40 wherein the cancer or inflammation is associated with hyperproliferation or cell survival.

43 . The method according to claim 40 wherein the hyperproliferative disease, cancer or inflammation is associated with the activity of SGK.

44 . (canceled)

45 . A method of treating a mammal having a disorder or condition associated with hyperproliferation and cell survival, wherein said method comprises administering to the mammal having the disorder or condition a therapeutically effective amount of a compound of formula (I):

wherein:

a is 0 to 4;

R 1 is carbocyclyl or heterocyclyl;

each R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, halo, haloalkyl, haloalkenyl, nitro, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, —OR 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —N(R 7 ) 2 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)R 7 , —R 9 —N═N—O—R 8 , —S(O) p R 7 (where p is 0 to 2), and —S(O) p N(R 7 ) 2 (where p is 0 to 2);

R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, halo, haloalkyl, haloalkenyl, nitro, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, —OR 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —N(R 7 ) 2 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)R 7 , —R 9 —N═N—O—R 8 , —S(O) p R 7 (where p is 0 to 2), and —S(O) p N(R 7 ) 2 (where p is 0 to 2);

R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkenyl and heterocyclylalkyl;

each R 7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl;

each R 8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl; and

R 9 is a bond or a straight or branched alkylene or alkenylene chain;

as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a solvate or polymorph; or as a pharmaceutically acceptable salt thereof.

46 . The method according to claim 40 or claim 45 wherein the mammal is a human.

47 . A method of treating a mammalian cell with a compound of formula (I):

wherein:

a is 0 to 4;

R 1 is carbocyclyl or heterocyclyl;

each R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, halo, haloalkyl, haloalkenyl, nitro, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, —OR 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —N(R 7 ) 2 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)R 7 , —R 9 —N═N—O—R 8 , —S(O) p R 7 (where p is 0 to 2), and —S(O) p N(R 7 ) 2 (where p is 0 to 2);

R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, halo, haloalkyl, haloalkenyl, nitro, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, —OR 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —N(R 7 ) 2 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)R 7 , —R 9 —N═N—O—R 8 , —S(O) p R 7 (where p is 0 to 2), and —S(O) p N(R 7 ) 2 (where p is 0 to 2);

R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkenyl and heterocyclylalkyl;

each R 7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl;

each R 8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl; and

R 9 is a bond or a straight or branched alkylene or alkenylene chain;

as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a solvate or polymorph; or as a pharmaceutically acceptable salt thereof, wherein the method comprises administering the compound of formula (I) to a mammalian cell and the compound of formula (I) is capable of inhibiting the activity of SGK within the mammalian cell.

48 . The method of claim 47 wherein the mammalian cell is treated in vitro.

49 . The method of claim 47 wherein the mammalian cell is treated in vivo.

50 . The method of claim 47 wherein the inhibition of activity results in a reduction of cell survival.

51 . The method of claim 47 wherein the inhibition of activity results in a reduction of cell division.

52 . The method of claim 47 , wherein the inhibition of activity results in apoptosis.

53 . The method of claim 47 , wherein the inhibition of activity results in control of tumour growth.

54 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 1 is carbocyclyl.

55 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 1 is aryl.

56 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 1 is cycloalkyl.

57 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 1 is heterocyclyl.

58 . The method or pharmaceutical composition of claim 1 or claim 40 wherein at least one R 2 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl.

59 . The method or pharmaceutical composition of claim 1 or claim 40 wherein at least one R 2 is aryl, aralkyl or aralkenyl.

60 . The method or pharmaceutical composition of claim 1 or claim 40 wherein at least one R 2 is halo, haloalkyl or haloalkenyl.

61 . The method or pharmaceutical composition of claim 1 or claim 40 wherein at least one R 2 is nitro, cyano, —N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)R 7 or —R 9 —N═N—O—R 8 .

62 . The method or pharmaceutical composition of claim 1 or claim 40 wherein at least one R 2 is heterocyclyl or heterocyclylalkyl.

63 . The method or pharmaceutical composition of claim 1 or claim 40 wherein at least one R 2 is —C(O)OR 7 or —C(O)N(R 7 ) 2 .

64 . The method or pharmaceutical composition of claim 1 or claim 40 wherein at least one R 2 is —OR 7 , —S(O) p R 7 (where p is 0 to 2), or —S(O) p N(R 7 ) 2 (where p is 0 to 2).

65 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 3 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl.

66 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 3 is aryl, aralkyl or aralkenyl.

67 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 3 is nitro, cyano, —N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)R 7 or —R 9 —N═N—O—R 8 .

68 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 3 is heterocyclyl or heterocyclylalkyl.

69 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 3 is —C(O)OR 7 or —C(O)N(R 7 ) 2 .

70 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 3 is —OR 7 , —S(O) p R 7 (where p is 0 to 2) or —S(O) p N(R 7 ) 2 (where p is 0 to 2).

71 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 4 is hydrogen, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl or cycloalkylalkenyl.

72 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 4 is aryl, aralkyl or aralkenyl.

73 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 4 is nitro, cyano, —N(R 7 ) 2 , —N(R 7 )C(O)OR 8 , —N(R 7 )C(O)R 7 or —R 9 —N═N—O—R 8 .

74 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 4 is heterocyclyl or heterocyclylalkyl.

75 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 4 is —C(O)OR 7 or —C(O)N(R 7 ) 2 .

76 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 4 is —OR 7 , —S(O) p R 7 (where p is 0 to 2) or —S(O) p N(R 7 ) 2 (where p is 0 to 2).

77 . The method or pharmaceutical composition of claim 1 or claim 40 wherein R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl or haloalkyl.