N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses

1. A method of treating a disorder selected from the group consisting of myelodysplastic syndrome, Parkinson's disease, complex regional pain syndrome, aphthous ulcers, cachexia, graft versus host disease, inflammation of the lungs, depression, atopic dermatitis, diabetic retinopathy, systemic lupus, and multiple sclerosis, in a mammal in need thereof comprising administering to said mammal an effective amount of a compound of formula I:

wherein:

Y is —C(O)—, —CH 2 —, or —CH 2 C(O)—;

R 1 and R 2 are each independently C 1-8 -alkyl, CF 2 H, CF 3 , CH 2 CHF 2 , cycloalkyl, or (C 1-8 -alkyl)cycloalkyl;

Z 1 is H, C 1-6 -alkyl, NH 2 , NR 3 R 4 or OR 5 ;

Z 2 is H or C(O)R 5 ;

X 1 , X 2 , X 3 and X 4 are each independently H, halogen, NO 2 , OR 3 , CF 3 , C 1-6 -alkyl, (C 0-4 -alkyl)-(C 3-6 -cycloalkyl), (C 0-4 -alkyl)-N—(R 8 R 9 ), (C 0-4 -alkyl)-NHC(O)—(R 8 ), (C 0-4 -alkyl)-NHC(O)CH(R 8 )(R 9 ), (C 0-4 -alkyl)-NHC(O)N(R 8 R 9 ), (C 0-4 -alkyl)-NHC(O)O(R 8 ), (C 0-4 -alkyl)-O—R 8 , (C 0-4 -alkyl)-imidazolyl, (C 0-4 -alkyl)-pyrrolyl, (C 0-4 -alkyl)-oxadiazolyl, (C 0-4 -alkyl)-triazolyl or (C 0-4 -alkyl)-heterocycle;

R 3 , R 4 , and R 5 are each independently H, C 1-6 -alkyl, O—C 1-6 -alkyl, phenyl, benzyl, or aryl;

R 6 and R 7 are independently H or C 1-6 -alkyl;

R 8 and R 9 are each independently H, C 1-9 -alkyl, C 3-6 -cycloalkyl, (C 1-6 -alkyl)-(C 3-6 -cycloalkyl), (C 0-6 -alkyl)-N(R 4 R 5 ), (C 1-6 -alkyl)-OR 5 , phenyl, benzyl, aryl, piperidinyl, piperazinyl, pyrrolidinyl, morpholino, or C 3-7 -heterocycloalkyl;

or a pharmaceutically acceptable salt thereof

or an enantiomer or diastereomer thereof.

2. The method of claim 1 , wherein the disorder is diabetic retinopathy.

3. The method of claim 1 , wherein the disorder is systemic lupus.

4. The method of claim 1 , wherein said disorder is myelodysplastic syndrome.

5. The method of claim 1 , wherein the disorder is aphthous ulcers.

6. The method of claim 1 , wherein the disorder is cachexia.

7. The method of claim 1 , wherein the disorder is graft versus host disease.

8. The method of claim 1 , wherein the disorder is atopic dermatitis.

9. The method of claim 1 , wherein the disorder is multiple sclerosis.

10. The method of claim 1 , wherein the compound is:

(3R)-(tert-Butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino (tert-butoxy)formate;

N-[3-(7-Amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propyl] (tert-butoxy)carbonylamino (tert-butoxy)formate;

(1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-amide;

(1R)—N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-acetamide;

(1R)—N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-Isobutyramide;

(1R)—N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-1,3-dioxo-2,3-dihydro-1H-Isoindol-4-yl}-acetamide;

(1R)—N-{2-[3-(N-Acetoxy-N-formyl-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-Isobutyramide;

(1R)—N-{2-[3-(N-Aminocarbonyl-N-hydroxy-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-Isobutyramide;

(1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-amide;

(N-{3-[7-(Cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}acetylamino) acetate;

(1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(formyl-hydroxy-amino)-butyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-amide; or

(3R)-(tert-Butoxy)-N-{3-(3-ethoxy-4-methoxyphenyl)-3-[7-nitro-1-oxoisoindolin-2-yl]-propyl}carbonylamino (tert-butoxy)formate.