Use of bi-aryl meta-pyrimidine inhibitors of kinases
The invention provides methods of treating a disease selected from systemic sclerosis, rheumatoid arthritis, mastocytosis, and chronic eosinophilic leukemia comprising administering biaryl meta-pyrimidine compounds having the general structure (A) to a subject in need thereof. The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the JAK kinase family, and various other specific receptor and non-receptor kinases.
1. A method for inhibiting JAK2 kinase activity in a subject wherein the subject has rheumatoid arthritis comprising administering to the subject with rheumatoid arthritis a therapeutically effective amount of at least one compound represented by structure (A):
wherein:
X is selected from the group consisting of a bond, O, and CH 2 ; Y is selected from the group consisting of a bond or NR 9 ; or X and Y taken together is a bond;
each R 9 is independently selected from H and C 1 -C 6 alkyl;
each of R 1 and R 2 is independently selected from H and C 1 -C 6 alkyl optionally substituted by halogen, amino or hydroxyl;
each of p, q, and n is independently selected from 0, 1, 2, 3, 4, 5, and 6;
G 0 is N or CH,
wherein when G 0 is N, each of R 3 and R 4 , taken together with G 0 , form a heterocyclic ring, wherein the formed heterocyclic ring is optionally substituted by one or two substitutents each independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, hydroxyl, or carboxyl, and
and wherein when G 0 =CH, then R 3 and R 4 , taken together with G 0 , form a heterocyclic ring wherein the formed heterocyclic ring is optionally substituted by one or two substitutents each independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, hydroxyl, or carboxyl;
G is CR 6′ where each R 6′ is independent of each other group R 6′ ; R 6′ is selected from the group consisting of H, halogen, C(O)—O-alkyl, alkyl, alkoxy, and haloalkyl or R 6′ is a bond when bonded to X;
A is NR 9 ;
R 5 is methyl;
wherein each of R 6 , R 7 , R 8 is independently selected for each occurrence from the group consisting of H, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, SO 2 H, SO 2 (C 1 -C 6 alkyl), SO 2 -heterocycle, SO 2 -cycloalkyl, —SO 2 NH(C 1 -C 6 alkyl), SO 2 N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), SO 2 NH(cycloalkyl), SO 2 NH-heterocycle, SO 2 NH(branched alkyl), NO 2 , CN, CONH 2 , CO—(C 1 -C 6 alkyl), COOH, COO—(C 1 -C 6 alkyl), and NHCO—(C 1 -C 6 alkyl), or R 6 and R 7 taken together, or R 7 and R 8 taken together, or R 6 and R 8 taken together form a moiety independently selected from the group consisting of —CH═CH—CH═CH— and —O—(CH 2 ) n —O—;
G 1 is CH; and
G 2 is CR 7 , with each group R 7 being independent of every other group R 7 ;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein A is NH.
3. The method of claim 2 , wherein at least one R 7 is SO 2 NH(t-butyl).
4. The method of claim 2 , wherein G 0 is N, and R 3 and R 4 are taken together with G 0 to form a heterocyclic ring.
5. The method of claim 4 , wherein R 3 and R 4 are taken together with G 0 to form a non-aromatic heterocyclic ring.
6. The method of claim 4 , wherein X and Y taken together is a bond, p, q, and n are each 0, and the heterocyclic ring is a piperazinyl substituted with methyl.
7. The method of claim 5 , wherein the compound, or a pharmaceutically acceptable salt thereof, administered is of the structure:
8. The method of claim 4 , wherein X is O, Y is a bond, p is 0, q and n are each 1, and the heterocyclic ring is an unsubstituted pyrrolidinyl.
9. The method of claim 8 , wherein the compound, or a pharmaceutically acceptable salt thereof, administered is of the structure:
10. The method of claim 1 , wherein R 6 , R 7 and R 8 are each independently selected from the group consisting of —CF 3 , —OCF 3 , —S(O 2 )—NH-t-butyl, and —NH—C(O)—CH 3 .
11. A method for inhibiting JAK2 kinase activity in a subject wherein the subject has rheumatoid arthritis comprising administering to the subject with rheumatoid arthritis a therapeutically effective amount of at least one compound comprising a first moiety chemically connected to a second moiety, or a pharmaceutically acceptable salt thereof, wherein the first moiety is selected from the group consisting of:
and wherein the second moiety is selected from the group consisting of:
12. The method of claim 1 , wherein the at least one compound of structure (A), or a pharmaceutically acceptable salt thereof, is in the form of a pharmaceutical composition which comprises at least one compound of structure (A) and a pharmaceutically acceptable carrier.
13. A method of inhibiting JAK2 kinase activity in a subject wherein the subject has rheumatoid arthritis, comprising administering to the subject with rheumatoid arthritis a therapeutically effective amount of a compound represented by:
or a pharmaceutically acceptable salt thereof.
14. A method of inhibiting JAK2 kinase activity in a subject wherein the subject has rheumatoid arthritis, comprising administering to the subject with rheumatoid arthritis a therapeutically effective amount of a compound represented by:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the at least one compound of structure (A) is selected from the group consisting of compounds having the formulae:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the at least one compound of structure (A) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the at least one compound of structure (A) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the at least one compound of structure (A) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein the at least one compound of structure (A) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 , wherein the at least one compound of structure (A) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 1 , wherein the at least one compound of structure (A) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
22. The method of claim 1 , wherein the at least one compound of structure (A) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
23. The method of claim 1 , wherein the at least one compound of structure (A) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
24. The method of claim 1 , wherein the at least one compound of structure (A) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
25. A method of inhibiting JAK2 kinase activity in a subject wherein the subject has rheumatoid arthritis, comprising administering to the subject with rheumatoid arthritis a compound selected from the group consisting of compounds having the formulae:
or a pharmaceutically acceptable salt thereof.
26. The method of claim 12 , wherein the pharmaceutical composition is administered orally.