Modified isoindolinones as glucosylceramide synthase inhibitors

A compound of the formula I:

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, hydroxy, —C1-C4alkylOH, or halo;
• Each X is independently —CRa—, or N;
• Ra is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, hydroxy, or halo;
• is phenyl, 2,3-dihydro-1H-benzo[d]imidazolyl, benzo[d][1,3]dioxolyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, phenylcarbonylamino, isoindolinyl, (benzo[d][1,3]dioxolyl)carbonylamino, quinuclidinyloxycarbonylamino, pyridylcarbonylamino, quinolinylcarbonylamino, (2,3-dihydro-1H-cyclopenta[b]quinolinyl)carbonylamino, (2,3-dihydrofuro[2,3-b]pyridinyl)carbonylamino, (dihydrobenzofuranyl)carbonylamino, (indolyl)carbonylamino, (indazolyl)carbonylamino, (2,3-dihydrobenzofuranyl)cabonylamino, (1H-pyrrolo[2,3-b]pyridinyl)carbonylamino, (2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl)carbonylamino, (2,3-dihydro-1H-indenyl)carbonylamino, (6,7-dihydro-5H-cyclopenta[b]pyridyl)ethenyl, (6,7-dihydro-5H-cyclopenta[b]pyridyl)carbonylamino, (benzo[d]thiazolyl)carbonylamino, (6,7-dihydro-5H-cyclopenta[b]pyridyl)ethenyl, (6,7-dihydro-5H-cyclopenta[b]pyridyl)ethyl, (6,7-dihydro-5H-cyclopenta[b]pyridyl)oxymethyl, (6,7-dihydro-5H-cyclopenta[b]pyridyl)methoxy, (6,7-dihydro-5H-cyclopenta[b]pyridyl)ethynyl, phenylethenyl, ([1,3]dioxolo[4,5-b]pyridyl)ethenyl, ([1,3]dioxolo[4,5-b]pyridyl)ethyl, ([1,3]dioxolo[4,5-b]pyridyl)carbonylamino, ([1,3]dioxolo[4,5-b]pyridyl)oxymethyl, ([1,3]dioxolo[4,5-b]pyridyl)methoxy, ([1,3]dioxolo[4,5-b]pyridyl)aminomethyl, (pyrazolo[1,5-a]pyridyl)carbonylamino, (pyrazolo[4,3-b]pyridyl)carbonylamino, or naphthyridinylcarbonylamino;
• each R2 is independently selected from fluoro, chloro, bromo, cyano, trifluromethyl, 2,2,2-trifluroethyl, methoxy, ethoxy, propoxy, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, oxo, phenyl, azaindolyl, benzoimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzo[d]isothiazole, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, 5H-pyrrolo[3,4-b]pyridine, thiazolyl, thienyl, triazolyl, triazinyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, isoquinolinyl, and oxazolyl, —(C0-C4 alkyl)O(C1-C4 fluoroalkyl), wherein each R2 is substituted with 0, 1, or 2 R5 substituents, each R5 is independently C1-C6alkyl, halo, hydroxy, or —(C1-C4 alkyl)OH;
• is 2-hydroxy-2-methylpropyl, 1-methyl-2-hydroxy-2-methylpropyl, cyclopentylethyl, 1-ethyl-2-hydroxy-2-methylpropyl, 2-hydroxyethyl, oxetanylmethyl, quinuclidinylethyl, cyclopropyl-2-methylpropyl, cyclopropylmethyl, methylisobutyl, cyclobutylmethyl, 1-cyclopropylethyl, cyclohexyl, phenyl, isobutyl, or oxetanylmethyl;
• each R3 is independently selected from trifluoromethyl, methyl, ethyl, hydroxy, methoxy, 2-hydroxy-propyl, hydroxymethyl, cyclopropyl, methoxymethyl and fluoro;
• and
• R4 is hydrogen, C1-C4 alkyl, or hydroxy.