Inhibitors of activin receptor-like kinase
Described herein are compounds that inhibit ALK2 and its mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.
1. A compound that is 6-halo-pyrrolo[1,2-b]pyridazin-4-ol, wherein halo is selected from Cl, Br, and I, or a pharmaceutically acceptable salt thereof.
2. A compound, wherein the compounds is 6-bromopyrrolo[1,2-b]pyridazin-4-ol, or a pharmaceutically acceptable salt thereof.
3. A method of synthesizing 6-halo-pyrrolo[1,2-b]pyridazin-4-ol, comprising the step of
combining a compound of Formula C-1:
with a compound of Formula D-1:
R 23 —O—NH 2 (D-1),
wherein:
R 21 is selected from chloro, bromo, and iodo;
R 22 is a leaving group; and
R 23 is an electron withdrawing group.
4. The method of claim 3 , wherein R 21 is bromo.
5. The method of claim 3 , wherein R 22 is selected from —N(R 24 )(R 25 ) and —OR 24 , wherein each of R 24 and R 25 is an independently selected C 1 -C 4 alkyl.
6. The method of claim 3 , wherein R 22 is —N(CH 3 ) 2 .
7. The method of claim 3 , wherein R 23 is selected from methylcarbonyl, t-butylcarbonyl, 4-nitrophenylcarbonyl, 4-cyanophenylcarbonyl, 4-trifluoromethylphenylcarbonyl, 4-fluorophenylcarbonyl, 4-trifluoromethylcarbonylphenylcarbonyl, 4-ethoxycarbonylphenylcarbonyl, 4-trifluoromethylsulfonylphenylcarbonyl, 2,4,6-trimethylphenylcarbonyl, 2,4,6-trimethyl-3,5-dinitrophenylcarbonyl, 2-trifluoromethyl-4-nitrophenyl, 2,4-dinitrophenyl, and diphenylphosphinyl.
8. The method of claim 3 , wherein R 23 is 4-nitrophenylcarbonyl.
9. The method of claim 3 , wherein the compound of Formula C-1 and the compound of Formula D-1 are dissolved in a polar solvent.
10. The method of claim 9 , wherein the polar solvent is selected from N-methyl-2-pyrrolidine (“NMP”), N,N-dimethylacetamide (“DMAC”), dimethylformamide (“DMF”), tetrahydrofuran (“THF”), methyl-tetrahydrofuran (“MeTHF”), dimethyl sulfoxide (“DMSO”), and cyclopentylmethyl ether (“CPME”).
11. The method of claim 9 , wherein the polar solvent is NMP or DMAC.
12. The method of claim 3 , wherein the compound of Formula C-1 is treated with a base.
13. The method of claim 12 , wherein the base is selected from KOC(CH 3 ) 3 , NaOC(CH 3 ) 3 , LiOC(CH 3 ) 3 , LiC(CH 3 ) 3 , Li(CH 2 ) 3 CH 3 , LiN(C 3 H 7 ) 2 , NaOCH 3 , NaOCH 2 CH 3 , KOCH 3 , LiOCH 3 , LiOCH 2 CH 3 , and KOCH 2 CH 3 .
14. The method of claim 12 , wherein the base is KOC(CH 3 ) 3 .
15. The method of claim 3 , wherein the method further comprises adding a protonating agent.
16. The method of claim 15 , wherein the protonating agent is selected from NH 4 Cl, NaHCO 3 , KHCO 3 , LiHCO 3 , acetic acid, HCl, HBr, and H 2 SO 4 .
17. The method of claim 15 , wherein the protonating agent is NH 4 Cl.