Protein kinase inhibitors
The present invention relates to a novel family of inhibitors of protein kinase of formula 1 and process for their production and pharmaceutical compositions thereof. In particular, the present invention relates to inhibitors of the members of the Tec, Src and Btk protein kinase families.
1. A method of inhibiting Btk kinase in a cell, the method comprising administering to a cell in need thereof a compound according to Formula 1:
wherein
R is selected from the group consisting of:
1) hydrogen,
2) alkyl,
3) heteroalkyl,
4) carbocyclyl,
5) heterocyclyl,
wherein the alkyl, heteroalkyl, carbocyclyl and heterocyclyl may be further substituted;
Y is
E is oxygen,
Z is
wherein Y-E-Z-W is
X 1 and X 2 are independently selected from hydrogen and halogen;
n is an integer from 0 to 2;
m is an integer from 0 to 2;
m′ is an integer from 0 to 2;
W is selected from the group consisting of:
1) halogen,
2) aralkyl,
3) heteroaralkyl,
4) —OR 3 ,
5) —OC(O)R 4 ,
6) —OC(O)NR 5 R 6 ,
7) —CH 2 O—R 4 ,
8) —NR 5 R 6 ,
9) —NR 2 C(O)R 4 ,
10) —NR 2 S(O) n R 4 ,
11) —NR 2 C(O)NR 5 R 6 ,
wherein the aralkyl and heteraralkyl may be further substituted;
R 2 is selected from the group consisting of hydrogen and alkyl;
R 3 is selected from the group consisting of substituted alkyl, unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
R 4 is selected from the group consisting of substituted alkyl, unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; and
R 5 and R 6 are (i) independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; or
(ii) fused to form a 3 to 8 membered heterocyclyl ring system;
or a pharmaceutically acceptable salt, or solvate thereof.
2. The method of claim 1 , wherein the cell is a cancer cell.
3. The method of claim 1 , wherein the cell is an immune cell.
4. A method of treating arthritis comprising administering to the subject a pharmaceutical composition comprising a compound of Formula 1
wherein
R is selected from the group consisting of:
6) hydrogen,
7) alkyl,
8) heteroalkyl,
9) carbocyclyl,
10) heterocyclyl,
wherein the alkyl, heteroalkyl, carbocyclyl and heterocyclyl may be further substituted;
Y is
E is oxygen,
Z is
wherein Y-E-Z-W is
X 1 and X 2 are independently selected from hydrogen and halogen;
n is an integer from 0 to 2;
m is an integer from 0 to 2;
m′ is an integer from 0 to 2;
W is selected from the group consisting of:
1) halogen,
2) aralkyl,
3) heteroaralkyl,
4) —OR 3 ,
5) —OC(O)R 4 ,
6) —OC(O)NR 5 R 6 ,
7) —CH 2 O—R 4 ,
8) —NR 5 R 6
9) —NR 2 C(O)R 4 ,
10) —NR 2 S(O) n R 4 ,
11) —NR 2 C(O)NR 5 R 6 ,
wherein the aralkyl and heteraralkyl may be further substituted;
R 2 is selected from the group consisting of hydrogen and alkyl;
R 3 is selected from the group consisting of substituted alkyl, unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
R 4 is selected from the group consisting of substituted alkyl, unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; and
R 5 and R 6 are (i) independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; or
(ii) fused to form a 3 to 8 membered heterocyclyl ring system,
or a pharmaceutically acceptable salt, or solvate thereof.
5. The method of claim 4 , wherein the pharmaceutical compositions may be in a conventional pharmaceutical form suitable for oral administration selected from tablets, capsules, granules, powders and syrups; parenteral administration as: intravenous, intramuscular, or subcutaneous injections; drop infusion preparations, inhalation, eye lotion, topical administration, ointment, or suppositories.
6. The method of claim 4 , wherein the compound of Formula 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered alone or in combination with one or more other active ingredients.
7. The method of claim 4 , wherein the compound is selected from
or a pharmaceutically acceptable salt, or solvate thereof.
8. The method of claim 6 , wherein the compound is selected from
or a pharmaceutically acceptable salt, or solvate thereof.