3-3-Di-Substituted-Oxindoles as Inhibitors of Translation Initiation

A method of inhibiting translation initiation in cells or inhibiting abnormal proliferation of cells comprising contacting the cells with a compound of formula II

• wherein R1 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, n-pentyl, cyclopentyl, hexyl, n-hexyl, cyclohexyl, heptyl, n-heptyl, cycloheptyl, methoxy, ethoxy. propoxy, butoxy, pentoxy, hexoxy, heptoxy or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetahydro-2H-pyran-2-yl;
• R2 is the same or different and is selected from hydrogen, hydroxyl, alkoxy, substituted alkoxy, methoxy, —O—CH2—R12, ethoxy, —O—CH2—CH2—R21, propargyloxy, 1H-1,2,3-triazol-1-yl, 4-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-1-yl, 4-((5-(2-hydroxyethylamino)pyridin-2-yl)methyl)-1H-1,2,3-triazol-1-yl) wherein R12 is 1H-1,2,3-triazol-4-yl, 1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl, carboxymethylene, 2-acetamide, N-(2-hydroxyethyl)-2-acetamido, N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido, wherein R21 is hydroxy, methoxy, amino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, [N-methyl,N-ethyl]amino, bromo, acetoxy, N-morpholino, N-pyrrolidino, N-piperidino, N-piperazino, N-[4-methyl]-piperazino, ((3R,4S,5S,6R)-2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl);
• R3 is hydrogen, fluorine, chlorine, bromine, iodine, trifluoroacetyl, 6-morpholinopyridin-3-yl, —NH2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, or heptoxy;
• R4 is the same or different and is selected from hydrogen, hydroxyl, methyl, fluorine, chlorine, bromine, iodine, —N(CH3)2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, morpholinomethyl, 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, or N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido;
• R5 is hydrogen or hydroxyl;
• R6 is oxygen, sulfur, NH, or CH2;
• R7 is O, SH, NH or CH3;
• and
• R8 is hydrogen, halogen, fluorine, chlorine, bromine, iodine, carboxylate, carboxylate alkyl ester, alkoxycarbonyl or methoxycarbonyl.

A method of inhibiting translation initiation in cells or inhibiting abnormal proliferation of cells comprising contacting the cells with a compound of formula III

• wherein R13 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, n-pentyl, cyclopentyl, hexyl, n-hexyl, cyclohexyl, heptyl, n-heptyl, cycloheptyl, methoxy, ethoxy. propoxy, butoxy, pentoxy, hexoxy, heptoxy or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetahydro-2H-pyran-2-yl.
• R14 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, n-pentyl, cyclopentyl, hexyl, n-hexyl, cyclohexyl, heptyl, n-heptyl, cycloheptyl, methoxy, ethoxy. propoxy, butoxy, pentoxy, hexoxy, heptoxy or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetahydro-2H-pyran-2-yl.
• R15 is hydrogen, hydroxyl, alkoxy, substituted alkoxy, methoxy, —O—CH2—R12, ethoxy, —O—CH2—CH2—R21, propargyloxy, 1H-1,2,3-triazol-1-yl, 4-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-1-yl, 4-((5-(2-hydroxyethylamino)pyridin-2-yl)methyl)-1H-1,2,3-triazol-1-yl) wherein R12 is 1H-1,2,3-triazol-4-yl, 1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl, carboxymethylene, 2-acetamide, N-(2-hydroxyethyl)-2-acetamido, N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido, wherein R21 is hydroxy, methoxy, amino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, [N-methyl,N-ethyl]amino, bromo, acetoxy, N-morpholino, N-pyrrolidino, N-piperidino, N-piperazino, N-[4-methyl]-piperazino, ((3R,4S,5S,6R)-2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl);
• and
• R16 is hydrogen, hydroxyl, alkoxy, substituted alkoxy, methoxy, —O—CH2—R12, ethoxy, —O—CH2—CH2—R21, propargyloxy, 1H-1,2,3-triazol-1-yl, 4-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-1-yl, 4-((5-(2-hydroxyethylamino)pyridin-2-yl)methyl)-1H-1,2,3-triazol-1-yl) wherein R12 is 1H-1,2,3-triazol-4-yl, 1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl, carboxymethylene, 2-acetamide, N-(2-hydroxyethyl)-2-acetamido, N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido, wherein R21 is hydroxy, methoxy, amino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, [N-methyl,N-ethyl]amino, bromo, acetoxy, N-morpholino, N-pyrrolidino, N-piperidino, N-piperazino, N-[4-methyl]-piperazino, ((3R,4S,5S,6R)-2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl).

A method of inhibiting translation initiation in cells or inhibiting abnormal proliferation of cells comprising contacting the cells with a compound of formula IV

• wherein R13 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, n-pentyl, cyclopentyl, hexyl, n-hexyl, cyclohexyl, heptyl, n-heptyl, cycloheptyl, methoxy, ethoxy. propoxy, butoxy, pentoxy, hexoxy, heptoxy or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetahydro-2H-pyran-2-yl;
• R16 is hydrogen, hydroxyl, alkoxy, substituted alkoxy, methoxy, —O—CH2—R12, ethoxy, —O—CH2—CH2—R21, propargyloxy, 1H-1,2,3-triazol-1-yl, 4-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-1-yl, 4-((5-(2-hydroxyethylamino)pyridin-2-yl)methyl)-1H-1,2,3-triazol-1-yl) wherein R12 is 1H-1,2,3-triazol-4-yl, 1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl, carboxymethylene, 2-acetamide, N-(2-hydroxyethyl)-2-acetamido, N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido, wherein R21 is hydroxy, methoxy, amino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, [N-methyl,N-ethyl]amino, bromo, acetoxy, N-morpholino, N-pyrrolidino, N-piperidino, N-piperazino, N-[4-methyl]-piperazino, ((3R,4S,5S,6R)-2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl);
• R17 is hydrogen, hydroxyl, methyl, fluorine, chlorine, bromine, iodine, —N(CH3)2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, morpholinomethyl, 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, or N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido;
• R18 is hydrogen, fluorine, chlorine, bromine, iodine, trifluoroacetyl, 6-morpholinopyridin-3-yl, —NH2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, or heptoxy.
• R19 is hydrogen, halogen, fluorine, chlorine, bromine, iodine, carboxylate, carboxylate alkyl ester, alkoxycarbonyl or methoxycarbonyl;
• and
• R20 is hydrogen, halogen, fluorine, chlorine, bromine, iodine, carboxylate, carboxylate alkyl ester, alkoxycarbonyl or methoxycarbonyl.

A method of inhibiting translation initiation in cells or inhibiting abnormal proliferation of cells comprising contacting the cells with a compound of formula V

• wherein R13 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, n-pentyl, cyclopentyl, hexyl, n-hexyl, cyclohexyl, heptyl, n-heptyl, cycloheptyl, methoxy, ethoxy. propoxy, butoxy, pentoxy, hexoxy, heptoxy or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetahydro-2H-pyran-2-yl;
• R16 is hydrogen, hydroxyl, alkoxy, substituted alkoxy, methoxy, —O—CH2—R12, ethoxy, —O—CH2—CH2—R21, propargyloxy, 1H-1,2,3-triazol-1-yl, 4-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-1-yl, 4-((5-(2-hydroxyethylamino)pyridin-2-yl)methyl)-1H-1,2,3-triazol-1-yl) wherein R12 is 1H-1,2,3-triazol-4-yl, 1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl, carboxymethylene, 2-acetamide, N-(2-hydroxyethyl)-2-acetamido, N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido, wherein R21 is hydroxy, methoxy, amino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, [N-methyl,N-ethyl]amino, bromo, acetoxy, N-morpholino, N-pyrrolidino, N-piperidino, N-piperazino, N-[4-methyl]-piperazino, ((3R,4S,5S,6R)-2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl);
• and
• R17 is hydrogen, hydroxyl, methyl, fluorine, chlorine, bromine, iodine, —N(CH3)2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, morpholinomethyl, 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, or N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido.

A method of inhibiting translation initiation in cells or inhibiting abnormal proliferation of cells comprising contacting the cells with a compound of formula VI

• wherein R1 is the same or different and is selected from hydrogen, halogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted alkenyl or heteroalkenyl, substituted or unsubstituted alkynyl or heteroalkynyl, cycloalkyl, —OR11 where R11 is substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted alkenyl or heteroalkenyl, or substituted or unsubstituted alkynyl or heteroalkynyl;
• exemplary R1 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, n-pentyl, cyclopentyl, hexyl, n-hexyl, cyclohexyl, heptyl, n-heptyl, cycloheptyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetahydro-2H-pyran-2-yl;
• R2 is the same or different and is selected from hydrogen, hydroxyl, alkoxy, substituted alkoxy, methoxy, —O—CH2—R12, ethoxy, —O—CH2—CH2—R21, —O—R22, propargyloxy, 1H-1,2,3-triazol-1-yl, 4-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-1-yl, 4-((5-(2-hydroxyethylamino)pyridin-2-yl)methyl)-1H-1,2,3-triazol-1-yl) wherein R12 is 1H-1,2,3-triazol-4-yl, 1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl, carboxymethylene, 2-acetamide, N-(2-hydroxyethyl)-2-acetamido, N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido, wherein R21 is hydroxy, methoxy, amino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, [N-methyl,N-ethyl]amino, bromo, acetoxy, N-morpholino, N-pyrrolidino, N-piperidino, N-piperazino, N-[4-methyl]-piperazino, ((3R,4S,5S,6R)-2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl), and wherein R22 is substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted alkenyl or heteroalkenyl, or substituted or unsubstituted alkynyl or heteroalkynyl, heterocycloalkyl linked to O with an alkyl, alkenyl or alkynyl group, branched or unbranched;
• R3 is hydrogen, halogen, —NH2, morpholino, morpholinoalkyl, morpholinomethyl, morpholinoethyl, pyridino, 6-morpholinopyridin-3-yl, —OR12 where R12 is substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted alkenyl or heteroalkenyl, or substituted or unsubstituted alkynyl, heteroalkynyl or R3 is connected to R10 wherein R3—X—R10 is S—C═N or N═C—S, such as thiazolo, exemplary R3 is hydrogen, fluorine, chlorine, bromine, iodine, trifluoroacetyl, 6-morpholinopyridin-3-yl, —NH2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, or heptoxy;
• R4 is the same or different and is selected from hydrogen, hydroxy, alkyl, methyl, ethyl, halogen, —N(CH3)2, alkoxy, heteroalkyl, or —OR12 where R12 is substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted alkenyl or heteroalkenyl, or substituted or unsubstituted alkynyl or heteroalkynyl, exemplary R4 is hydrogen, hydroxyl, methyl, fluorine, chlorine, bromine, iodine, —N(CH3)2, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, morpholinomethyl, 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl, or N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido;
• R5 is hydrogen or hydroxy;
• R6 is oxygen, sulfur, NH or CH2;
• R8 is hydrogen, halogen, fluorine, chlorine, bromine, iodine, carboxylate, carboxylate alkyl ester, alkoxycarbonyl or methoxycarbonyl;
• R9 is hydrogen, halogen, fluorine, chlorine, bromine, iodine, carboxylate, carboxylate alkyl ester, alkoxycarbonyl or methoxycarbonyl;
• R10 is hydrogen or R10 is connected to R3 wherein R10—X—R3 is S—C═N or N═C—S;
• and
• R23 is hydrogen, 2-bromoethyl, 2(N,N-dimethylamino)ethyl, 2(N,N-diethylamino)ethyl, 2-(pyrrolidin-1-yl)ethyl, 2-morpholinoethyl, 2-(piperazin-1-yl)ethyl or 2-(4-methylpiperazin-1-yl)ethyl.

A method of inhibiting translation initiation in cells or inhibiting abnormal proliferation of cells comprising contacting the cells with a compound of formula VII

• wherein R13 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, n-pentyl, cyclopentyl, hexyl, n-hexyl, cyclohexyl, heptyl, n-heptyl, cycloheptyl, methoxy, ethoxy. propoxy, butoxy, pentoxy, hexoxy, heptoxy or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetahydro-2H-pyran-2-yl.
• R16 is hydrogen, hydroxyl, alkoxy, substituted alkoxy, methoxy, —O—CH2—R12, ethoxy, —O—CH2—CH2—R21, propargyloxy, 1H-1,2,3-triazol-1-yl, 4-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-1-yl, 4-((5-(2-hydroxyethylamino)pyridin-2-yl)methyl)-1H-1,2,3-triazol-1-yl) wherein R12 is 1H-1,2,3-triazol-4-yl, 1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl, carboxymethylene, 2-acetamide, N-(2-hydroxyethyl)-2-acetamido, N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido, wherein R21 is hydroxy, methoxy, amino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, [N-methyl,N-ethyl]amino, bromo, acetoxy, N-morpholino, N-pyrrolidino, N-piperidino, N-piperazino, N-[4-methyl]-piperazino, ((3R,4S,5S,6R)-2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl);
• and
• R5 is hydrogen or hydroxyl.

A method of inhibiting translation initiation in cells or inhibiting abnormal proliferation of cells comprising contacting the cells with a compound of formula VIII

• wherein R13 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, n-pentyl, cyclopentyl, hexyl, n-hexyl, cyclohexyl, heptyl, n-heptyl, cycloheptyl, methoxy, ethoxy. propoxy, butoxy, pentoxy, hexoxy, heptoxy or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetahydro-2H-pyran-2-yl.
• R16 is hydrogen, hydroxyl, alkoxy, substituted alkoxy, methoxy, —O—CH2—R12, ethoxy, —O—CH2—CH2—R21, propargyloxy, 1H-1,2,3-triazol-1-yl, 4-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-1-yl, 4-((5-(2-hydroxyethylamino)pyridin-2-yl)methyl)-1H-1,2,3-triazol-1-yl) wherein R12 is 1H-1,2,3-triazol-4-yl, 1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl, carboxymethylene, 2-acetamide, N-(2-hydroxyethyl)-2-acetamido, N-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)acetamido, wherein R21 is hydroxy, methoxy, amino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, [N-methyl,N-ethyl]amino, bromo, acetoxy, N-morpholino, N-pyrrolidino, N-piperidino, N-piperazino, N-[4-methyl]-piperazino, ((3R,4S,5S,6R)-2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) or 2-oxy-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl);
• and
• R5 is hydrogen or hydroxyl.