Imidazolin-5-one derivative useful as fasn inhibitors for the treatment of cancer

A method of treating a disorder mediated by inhibition of fatty acid synthase (FASN) enzyme comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I)

• wherein
• R1 is C1-4alkyl and fluorinated C1-2alkyl;
• R2 is selected from the group consisting of C1-4alkyl, fluorinated C1-2alkyl, —(C1-4alkyl)-O—(C1-4alkyl), (C3-6cycloalkyl, phenyl and 5 to 6 membered heteroaryl;
• wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy and cyano;
• m is an integer from 0 to 1;
• and n is an integer from 0 to 1;
• provided that each of m and n are not 1;
• is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl and piperidin-4-yl;
• R3 is selected from the group consisting of C1-4alkyl, fluorinated C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, —(C1-4alkyl)-(C3-6cycloalkyl), 4 to 6 membered, saturated heterocyclyl, —(C1-4alkyl)-(4 to 6 membered, saturated heterocyclyl), 5 to 6 membered heteroaryl and —(C1-4alkyl)-(5 to 6 membered heteroaryl);
• wherein the C3-6cycloalkyl, 4 to 6 membered, saturated heterocyclyl or 5 to 6 membered heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy and NRARB;
• wherein RA and RB are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• a is an integer from 0 to 2;
• each R4 is independently selected from the group consisting of hydroxy, halogen, C,1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, and NRCRD;
• wherein RC and RD are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• R5 is selected from the group consisting of aryl and heteroaryl;
• wherein the aryl or heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, halogen, cyano, nitro, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, NRERF, —(C1-4alkyl)-NRERF, —C(O)—(C1-4alkyl), —C(O)—NRERF, —C(O)OH, —C(O)O—(C1-4alkyl), —NRE—C(O)—(C1-4alkyl) and —NRE—SO2—(C1-4alkyl);
• wherein RE and RF are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• alternatively, R5 is
• wherein R6 is selected from the group consisting of phenyl and 5 to 6 membered heteroaryl;
• wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with with one to two substituents independently selected from the group consisting of hydroxy, halogen, cyano, nitro, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, NRGRH, —C(O)—NRGRH, —C(O)OH, —C(O)O—(C1-4alkyl) and —(C1-4alkyl)-NRGRH;
• wherein RG and RH are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

A method of treating

• (a) cancer of the breast, prostate, head, neck, skin, lung, ovary, endometrium, thyroid, colon, rectum, esophagus, stomach, kidney, liver, bladder, pancreas, brain, spinal cord, blood or bone;
• (b) obesity or a related disorder selected from the group consisting of obesity, overweight, weight gain, Type II diabetes mellitus, Syndrome X, and appetite or satiety modulation;
• or (c) a liver related disorders selected from the group consisting of dyslipidemia, elevated cholesterol levels, elevated LDL, decreased HDL, elevated triglicerides, fatty liver, non-alcoholic steatohepatitis (NASH), fatty liver and non-alcoholic fatty liver disease (NAFLD);
• comprising, consisting of and/or consisting essentially of administering to a subject in need thereof, a therapeutically effective amount of a compound formula (I)
• wherein
• R1 is C1-4alkyl and fluorinated C1-2alkyl;
• R2 is selected from the group consisting of C1-4alkyl, fluorinated C1-2alkyl, —(C1-4alkyl)-O—(C1-4alkyl), C3-6cycloalkyl, phenyl and 5 to 6 membered heteroaryl;
• wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy and cyano;
• m is an integer from 0 to 1;
• and n is an integer from 0 to 1;
• provided that each of m and n are not 1;
• is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl and piperidin-4-yl;
• R3 is selected from the group consisting of C1-4alkyl, fluorinated C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, —(C1-4alkyl)-(C3-6cycloalkyl), 4 to 6 membered, saturated heterocyclyl, —(C1-4alkyl)-(4 to 6 membered, saturated heterocyclyl), 5 to 6 membered heteroaryl and —(C1-4alkyl)-5 to 6 membered heteroaryl);
• wherein the C3-6cycloalkyl, 4 to 6 membered, saturated heterocyclyl or 5 to 6 membered heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy and NRARB;
• wherein RA and RB are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• a is an integer from 0 to 2;
• each R4 is independently selected from the group consisting of hydroxy, halogen, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, and NRCRD;
• wherein RC and RD are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• R5 is selected from the group consisting of aryl and heteroaryl;
• wherein the aryl or heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, halogen, cyano, nitro, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, NRERF, —(C1-4alkyl)-NRERF, —C(O)—(C1-4alkyl), —C(O)—NRERF, —C(O)OH, —C(O)O—(C1-4alkyl), —NRE—C(O)—(C1-4alkyl) and —NRE—SO2—(C14alkyl);
• wherein RE and RF are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• alternatively, R5 is
• wherein R6 is selected from the group consisting of phenyl and 5 to 6 membered heteroaryl;
• wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with with one to two substituents independently selected from the group consisting of hydroxy, halogen, cyano, nitro, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, NRGRH, —C(O)—NRGRH, —C(O)OH, —C(O)O—(C1-4alkyl) and —(C1-4alkyl)-NRGRH;
• wherein RG and RH are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

A method of treating

• (a) cancer of the breast, prostate, head, neck, skin, lung, ovary, endometrium, thyroid, colon, rectum, esophagus, stomach, kidney, liver, bladder, pancreas, brain, spinal cord, blood or bone;
• (b) obesity or a related disorder selected from the group consisting of obesity, overweight, weight gain, Type II diabetes mellitus, Syndrome X, and appetite or satiety modulation;
• or (c) a liver related disorders selected from the group consisting of dyslipidemia, elevated cholesterol levels, elevated LDL, decreased HDL, elevated triglicerides, fatty liver, non-alcoholic steatohepatitis (NASH), fatty liver and non-alcoholic fatty liver disease (NAFLD);
• comprising, consisting of and/or consisting essentially of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound compound of formula (I)
• wherein
• R1 is C1-4alkyl and fluorinated C1-2alkyl;
• R2 is selected from the group consisting of C1-4alkyl, fluorinated C1-2alkyl, —(C1-4alkyl)-O—(C1-4alkyl), C3-6cycloalkyl, phenyl and 5 to 6 membered heteroaryl;
• wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy and cyano;
• m is an integer from 0 to 1;
• and n is an integer from 0 to 1;
• provided that each of m and n are not 1;
• is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl and piperidin-4-yl;
• R3 is selected from the group consisting of C1-4alkyl, fluorinated C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, —(C1-4alkyl)-(C3-6cycloalkyl), 4 to 6 membered, saturated heterocyclyl, —(C1-4alkyl)-(4 to 6 membered, saturated heterocyclyl), 5 to 6 membered heteroaryl and —(C1-4alkyl)-(5 to 6 membered heteroaryl);
• wherein the C3-6cycloalkyl, 4 to 6 membered, saturated heterocyclyl or 5 to 6 membered heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy and NRARB;
• wherein RA and RB are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• a is an integer from 0 to 2;
• each R4 is independently selected from the group consisting of hydroxy, halogen, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, and NRCRD;
• wherein RC and RD are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• R5 is selected from the group consisting of aryl and heteroaryl;
• wherein the aryl or heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, halogen, cyano, nitro, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, NRERF, —(C1-4alkyl)-NRERF, —C(O)—(C1-4alkyl), —C(O)—NRERF, —C(O)OH, —C(O)O—(C1-4alkyl), —NRE—C(O)—(C1-4alkyl) and —NRE—SO2—(C14alkyl);
• wherein RE and RF are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• alternatively, R5 is
• wherein R6 is selected from the group consisting of phenyl and 5 to 6 membered heteroaryl;
• wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, halogen, cyano, nitro, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, NRGRH, —C(O)—NRGRH, —C(O)OH, —C(O)O—(C1-4alkyl) and (C1-4alkyl)-NRGRH;
• wherein RG and RH are each independently selected from the group consisting of hydrogen and C1-4alkyl;
• or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.