4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (CML)

1. A method of treating or inhibiting the proliferation of CML comprising, providing to a patient in need thereof a therapeutically effective amount of a compound of the formula:

wherein:

n is an integer from 1-3;

X is N, CH, provided that when X is N, n is 2 or 3;

R is alkyl of 1 to 3 carbon atoms;

R 1 is 2,4-diCl, 5-OMe; 2,4-diCl; 3,4,5-tri-OMe; 2-Cl, 5-OMe; 2-Me, 5-OMe; 2,4-di-Me; 2,4-diMe-5-OMe, 2,4-diCl, 5-OEt;

R 2 is alkyl of 1 to 2 carbon atoms, and pharmaceutically acceptable salts thereof.

2. The method of claim 1 wherein the compound is of the formula:

wherein:

n is an integer from 2-3;

X is N, CH, provided that when X is N, n is 2 or 3;

R is alkyl of 1 to 3 carbon atoms;

R 1 is 2,4-diCl, 5-OMe; 2,4-diCl; 3,4,5-tri-OMe; 2-Cl, 5-OMe; 2-Me, 5-OMe; 2,4-di-Me; 2,4-diMe-5-OMe, 2,4-diCl, 5-OEt;

R 2 is alkyl of 1 to 2 carbon atoms, and pharmaceutically acceptable salts thereof.

3. The method of claim 1 wherein the compound is of the formula:

X is N, CH

n is 3;

R 2 and R are methyl; and pharmaceutically acceptable salts thereof.

4. The method of claim 1 wherein R 2 is methyl.

5. The method of claim 1 wherein X is N.

6. The method of claim 1 wherein X is CH.

7. The method of claim 1 wherein the compound is: 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile.

8. The method of claim 1 wherein the compound is:

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[3-(4-ethyl-1-piperazinyl)propoxy]-6-methoxy-3-quinolinecarbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]-3-quinolinecarbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[2-(4-ethyl-1-piperazinyl)ethoxy]-6-methoxy-3-quinolinecarbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-3-quinolinecarbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]-3-quinolinecarbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[(1 -ethylpiperidin-4-yl)methoxy]-6-methoxyquinoline-3-carbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(4-ethylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]quinoline-3-carbonitrile;

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinoline-3-carbonitrile; or

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-propyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile; and pharmaceutically acceptable salts thereof.

9. The method of claim 1 wherein the compound is:

4-[(2,4-dichlorophenyl)amino]-6-methoxy-7-[(1 -methylpiperidin-4-yl)methoxy]-3-quinolinecarbonitrile;

6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-4-[(3,4,5-trimethoxyphenyl)amino]quinoline-3-carbonitrile;

4-[(2-chloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile;

6-methoxy-4-[(5-methoxy-2-methylphenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile;

4-[(2,4-dimethylphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile;

6-methoxy-4-[(5-methoxy-2,4-dimethylphenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; and

4-[(2,4-dichloro-5-ethoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile.

10. The method of claim 1 wherein the compound is a Src inhibitor and a Abl Kinase inhibitor.

11. The method of claim 1 wherein the compounds are delivered alone or in combination with other compounds used to treat CML.

12. The method of claim 11 wherein the combination compound is (Imatinib)

4-[(4-methyl-1piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2pyrimidinyl]amino]phenyl]-Benzamide.