Pyrimid-2-yl-pyrazole compounds as IRAK inhibitors

Patent metadata

Field	Value
Publication number	US-12384775-B2
Application number	US-202318187789-A
Country	US
Kind code	B2
Filing date	Mar 22, 2023
Priority date	Mar 23, 2022
Publication date	Aug 12, 2025
Grant date	Aug 12, 2025

Abstract

Disclosed embodiments concern novel interleukin receptor associated kinases (IRAK) inhibitor compounds and compositions comprising such compounds. The compounds may have a structure according to Formula IAlso disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.

First claim

We claim:

1. A compound having a structure according to Formula I

or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 is H, aliphatic, or alkyl phosphate;
R 2 is C 1-6 alkyl.

2. The compound of claim 1 , wherein R 1 is H, alkyl, or -alkylOP(O)(OR) 2 , where each OR is —OH, —Oalkyl, —Oaryl, —Oheteroaryl, —Oaralkyl, or —OM + where M + is a counter ion with a single positive charge.

3. The compound of claim 2 , wherein R 1 is —CH(CH 3 )OP(O)(OR) 2 or —CH 2 OP(O)(OR) 2 .

4. The compound of claim 1 , wherein R 2 is C 1-4 alkyl.

5. The compound of claim 1 , wherein the compound has a structure according to Formula II

or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 5 , wherein R 1 is wherein R 1 is H or C 1-4 alkyl phosphate.

7. The compound of claim 5 , wherein R 1 is —CH 2 OP(O)(OH) 2 , —CH(CH 3 )OP(O)(OH) 2 , or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein R 1 is H, or C 1-4 alkyl phosphate.

9. The compound of claim 2 , wherein R 1 is —CH 2 OP(O)(OR) 2 .

10. The compound of claim 9 , wherein:
R 1 is —CH 2 OP(O)(OH) 2 ;
R 1 is —CH 2 OP(O) (OC 1-6 alkyl) 2 ; or
R 1 is —CH 2 OP(O) (O − M + ) 2 .

11. The compound of claim 10 , wherein R 1 is —CH 2 OP(O)(O − Na + ) 2 .

12. The compound of claim 1 , wherein the compound is a salt co-crystal.

13. The compound of claim 1 , wherein the compound is in a free base form.

14. The compound of claim 12 , wherein the salt co-crystal is a tartaric acid salt co-crystal or a tris salt co-crystal.

15. The compound of claim 1 , selected from:
I-1: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl) thiazole-4-carboxamide;
I-2: (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl) carbamoyl) thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
I-3: sodium (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl) carbamoyl) thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate;
I-4: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl) thiazole-4-carboxamide tartaric acid salt;
I-5: (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl) carbamoyl) thiazol-2-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate 1,3-dihydroxy-2-(hydroxymethyl) propan-2-aminium (tris salt);
I-6:1-(4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl) carbamoyl) thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate;
I-7: sodium 1-(4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl) carbamoyl) thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate; and
I-8:1-(4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl) carbamoyl) thiazol-2-yl)-1H-pyrazol-1-yl)ethyl hydrogen phosphate 1,3-dihydroxy-2-(hydroxymethyl) propan-2-aminium (tris salt).

16. The compound of claim 15 , wherein the compound is I-1: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl) thiazole-4-carboxamide.

17. The compound of claim 15 , wherein the compound is I-2: (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl) carbamoyl) thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate.

18. The compound of claim 15 , wherein the compound is I-3: sodium (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl) carbamoyl) thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate.

19. A compound that is I-1: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl) thiazole-4-carboxamide or a pharmaceutically acceptable salt or solvate thereof.

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

21. A pharmaceutical composition, comprising:
a means for delivering an IRAK inhibitory moiety, wherein the IRAK inhibitory moiety comprises the compound of claim 1 ; and
a pharmaceutically acceptable excipient.

22. The pharmaceutical composition of claim 21 , wherein the means for delivering an IRAK inhibitory moiety comprises a means for inhibiting an IRAK protein in vivo.

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Maung Jack
• Chen Yan
• Shaw Simon
• Sweeny David
• Masuda Esteban

Classifications

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title