Cyclohexyl sulphones for treatment of cancer

1. A method of treating a cancer associated with modified Notch signaling in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of formula I:

wherein:

m is 0 or 1;

Z represents CN, OR 2a , CO 2 R 2a or CON(R 2a ) 2 ;

R 1b represents H, C 1-4 alkyl or OH;

R 1c represents H or C 1-4 alkyl,

Ar 1 represents phenyl or pyridyl, either of which bears 0-3 substituents independently selected from halogen, CN, NO 2 , CF 3 , OH, OCF 3 , C 1-4 -alkoxy or C 1-4 alkyl which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH and C 1-4 alkoxy;

Ar 2 represents phenyl which is substituted in the 2- and 5-positions with halogen;

R 2a represents H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, any of which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OR 2b , CO 2 R 2b , N(R 2b ) 2 , CON(R 2b ) 2 , Ar and COAr; or R 2a represents Ar; or two R 2a groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-4 substituents independently selected from ═O, ═S, halogen, C 1-4 alkyl, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, CO 2 H, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, Ar and COAr;

R 2b represents H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, any of which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C alkoxycarbonyl, CO 2 H, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, Ar and COAr; or R 2b represents Ar; or two R 2b groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-4 substituents independently selected from ═O, ═S, halogen, C 1-4 alkyl, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, CO 2 H, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, Ar and COAr;

Ar represents phenyl or heteroaryl bearing 0-3 substituents selected from halogen, C 1-4 alkyl, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, C 1-4 alkylcarbamoyl and di(C 1-4 alkyl)carbamoyl;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein Ar 1 is selected from phenyl groups substituted in the 4-position with halogen, methyl or trifluoromethyl, and phenyl groups substituted in the 3- and 4-positions by halogen.

3. The method according to claim 2 wherein Ar 1 is 4-chlorophenyl or 4-trifluoromethylphenyl and Ar 2 is 2,5-difluorophenyl.

4. The method according to claim 3 wherein m is 1, R 1b and R 1c both represent H, and Z represents R 2a .

5. The method according to claim 3 wherein m is O, R 1c represents H and Z represents CON(R 2a ) 2 .

6. The method according to claim 4 wherein R 2a represents H or C 1-6 alkyl.

7. The method according to claim 1 wherein the cancer is selected from breast, prostate, colon, ovarian, colorectal and lung cancers.

8. The method according to claim 1 wherein the cancer is lymphoma or leukemia.

9. The method according to claim 8 wherein the cancer is T-ALL.

10. The method according to claim 1 wherein the compound of formula I is administered in combination with another anti-cancer agent or therapeutic agent, optionally in conjunction with radiation therapy.

11. The method according to claim 10 wherein said other anti-cancer agent or therapeutic agent is selected from the group consisting of: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, a γ-secretase and/or NOTCH inhibitor, an agent that interferes with receptor tyrosine kinases (RTKs), and an agent that interferes with a cell cycle checkpoint.

12. The method according to claim 1 wherein m is 1, Z represents CO 2 R 2a , R 1b represents H, R 1C represents H, Ar 1 represents 4-chlorophenyl, Ar 2 represents 2,5-difluorophenyl, and R 2a represents H.