IP Library › Granted Patent US 10,710,983

Granted Patent B2

US 10,710,983 · App. 15/633,258 · Granted Jul 14, 2020

2,4-diamino-pyrimidine compounds and method for making and using the compounds

Inventors: Yan Chen (Foster City, CA); Rose Yen (San Francisco, CA); Jiaxin Yu (Foster City, CA); Vanessa Taylor (San Francisco, CA); Rajinder Singh (Belmont, CA)

Assignee: Rigel Pharmaceuticals, Inc.

C07D403/12 C07D239/48 C07D401/14 C07D405/14

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 10,710,983
App. No.: 15/633,258
Granted: Jul 14, 2020
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Compounds within the scope of the present invention have a Formula 1 or a salt or prodrug 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.

Claims (102)

1. A compound having a formula 1

or salt thereof, wherein:

ring A is cycloaliphatic;

ring B is selected from

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.

2. The compound according to claim 1 , wherein cycloaliphatic ring A is substituted with —CONH 2 .

3. The compound according to claim 2 , wherein ring A is a carboxamide substituted (C6-C12) cycloalkyl, (C6-C12) cycloalkenyl, (C6-C12) bicycloalkyl or a (C6-C12) bicycloalkenyl ring.

4. A compound having a formula 1,

or salt thereof, wherein:

ring A is selected from

ring B is selected from

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.

5. The compound according to claim 1 , wherein R 1 is aryl or heteroaryl.

6. The compound according to claim 1 , wherein R 1 is CH 3 ,

7. 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 .

8. The compound according to claim 7 , having a formula

9. The compound according to claim 1 , having a formula selected from

wherein the A ring, the B ring, R 2 and R 3 are as stated in claim 1 , and R 4 is selected from (C1-C6)alkyl, cyano, halo and hydrogen.

10. The compound according to claim 9 , wherein R 4 is methyl.

11. The compound according to claim 9 , where R 4 is fluoro.

12. 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 .

13. The compound according to claim 12 , wherein (C1-C10)alkyl is methyl.

14. The compound according to claim 12 , wherein (C3-C10)cycloalkyl is cyclopropyl.

15. The compound according to claim 1 , having an IRAK4 IC 50 of from 0.003 μM to 3.7 μM.

16. The compound according to claim 1 , having a TAK1 IC 50 of from 0.008 μM to 132 μM.

17. The compound according to claim 1 , having an IRAK4/TAK1 selectivity of from 1 to 450.

18. The compound according to claim 1 , comprising a 5-aryl-substituted pyrimidinediamine having a IRAK4/TAK1 selectivity of from 100 to 500.

19. The compound according to claim 1 , comprising a 5-halophenyl-substituted pyrimidinediamine having an IRAK4/TAK1 selectivity of greater than 400.

20. The compound according to claim 1 , comprising a 5-cyanophenyl-substituted pyrimidinediamine having an IRAK4/TAK1 selectivity of greater than 150.

21. A compound, selected from:

(1S,2S,3R,4R)-3-((5-(pyridin-3-yl)-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-((2-((3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-5-(pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(pyridin-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-methyl-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-cyclopropyl-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(furan-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-phenyl-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(pyridin-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(pyridin-4-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(2-fluorophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(3-fluorophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(4-fluorophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(3-cyanophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-(4-cyanophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(5-fluoropyridin-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(2-fluoropyridin-4-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

1S,2R)-2-((5-(3-cyanophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide;

(1S,2S,3R,4R)-3-((5-bromo-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide; or

(1S,2S,3R,4R)-3-((5-bromo-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide.

22. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

23. A method for inhibiting IRAK and/or TAK proteins, comprising contacting an IRAK protein, a TAK protein, or both, with an effective amount of a compound of claim 1 .

24. The method according to claim 23 , comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

25. The method according to claim 23 , wherein the IRAK protein is IRAK4.

26. The method according to claim 23 , wherein the TAK protein is TAK1.

27. A pharmaceutical composition, comprising:

a pharmaceutically acceptable excipient; and

a compound selected from