2,4-diamino-pyrimidine compounds and method for making and using the compounds
Compounds within the scope of the present invention have a Formula 1 or a salt or produg thereof, where ring A is selected from cycloaliphatic; ring B is aryl; R 1 is selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, halo, aryl, and heteroaryl; and R 2 and R 3 are independently selected from hydrogen and (C1-C6)alkyl. Disclosed compounds may have an IRAK4 IC 50 of from 0.003 μM to 3.7 μM; a TAK1 IC 50 of from 0.008 μM to 132 μM; and/or an IRAK4/TAK1 selectivity of from 1 to 450. Particular compounds may have an IRAK4/TAK1 selectivity of from 100 to 500. Disclosed compositions may be formulated as pharmaceutical compositions. A method for using the compounds and/or compositions also are disclosed. The method may comprise administering to a subject an effective amount of a compound within the scope of the present invention, particularly to selectively inhibit IRAK 1 and/or IRAK4 over TAK1.
1. A compound having a formula 1
or salt thereof, wherein:
ring A is a carboxamide substituted (C6-C12) cycloalkyl, (C6-C12) cycloalkenyl, (C6-C12) bicycloalkyl or a (C6-C12) bicycloalkenyl ring;
ring B is aryl;
R 1 is (C4-C10)alkyl, (C4-C10)cycloalkyl, aryl, or heteroaryl, wherein if R 1 is pyridinyl then the A ring is other than cyclohexyl; and
R 2 and R 3 are independently hydrogen or (C1-C6)alkyl.
2. The compound according to claim 1 , wherein cycloaliphatic ring A is substituted with —CONH 2 .
3. The compound according to claim 1 , wherein ring B is a mono-, di- or tri-substituted phenyl ring.
4. The compound according to claim 1 , wherein ring B is substituted with a substituent selected from (C1-10)amide, (C3-C10)cycloamide, (C1-C10)alkyl, (C1-C10)alkoxyl, (C3-C10)cycloalkoxyl, halo, (C3-C10)cycloalkyl or (C3-C10)heterocycloalkyl.
5. The compound according to claim 4 , wherein the substituent is methyl or fluoro.
6. The compound according to claim 1 , wherein the A ring is selected from
7. The compound according to claim 1 , wherein the B ring is selected from
8. The compound according to claim 1 , wherein R 1 is aryl or heteroaryl.
9. A compound, having a formula
or salt thereof, wherein:
ring A is cycloaliphatic;
ring B is aryl;
R 1 is
and
R 2 and R 3 are independently hydrogen or (C1-C6)alkyl.
10. The compounds according to claim 1 , having a formula selected from
wherein the A ring, the B ring, R 1 , R 2 and R 3 are as stated in claim 1 .
11. A compound, having a formula
wherein:
ring B is aryl;
R 1 is (C1-C10)alkyl, (C3-C10)cycloalkyl, aryl, or heteroaryl; and
R 2 and R 3 are independently hydrogen or (C1-C6)alkyl.
12. A compound, having a formula selected from
wherein:
the A ring is cycloaliphatic;
the B ring is aryl;
R 2 and R 3 are independently hydrogen or (C1-C6)alkyl; and
R 4 is selected from (C1-C6)alkyl, cyano, halo and hydrogen.
13. The compound according to claim 12 , wherein R 4 is methyl or fluoro.
14. The compound according to claim 1 , having a formula selected from
wherein the A ring, the B ring, and R 2 and R 3 are as stated in claim 1 .
15. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
16. A method for inhibiting a protein, comprising contacting an IRAK or TAK protein with an effective amount of a compound of claim 1 .
17. The method according to claim 16 , comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .
18. The method according to claim 16 , wherein the IRAK protein is IRAK4, and the TAK protein is TAK1.